Hypolipidemic alkenesulfonamides

ABSTRACT

Method for lowering blood liped levels in mammals, using certain derivatives of N-carbamoyl-2-phenylethenesulfonamide, many of which are novel.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of co-pending application,Ser. No. 422,088, filed Dec. 5, 1973, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a new method for reducing elevated serum lipidlevels in mammals. Atherosclerosis, which is a form of arteriosclerosis,is rapidly becoming recognized as a major health problem today. Thedisease is characterized by deposition of lipids in the aorta, and inthe cornonary, cerebral and peripheral arteries of the lowerextremities. As the deposits increase, the danger of thrombus formationand occlusion exists. Although the origins of atherosclerosis are notfully understood, it has been observed that many people suffering fromthis disease exhibit elevated plasma lipid protein levels, of whichcholesterol and triglycerides are major components. Despite the factthat dietary habits can contribute to lowering plasma lipoproteinlevels, several therapeutic agents, such as estrogens, thyroxinanalogues and sitosterol preparations have been employed for thispurpose. Recently, ethyl 2-(p-chlorophenoxy)isobutyrate (clofibrate) hasbeen shown to be an effective agent for reducing elevated triglyceridelevels in humans.

This invention also relates to certain novel chemical compounds, usefulfor reducing serum lipid levels in mammals. These novel chemicalcompounds are derivatives of N-carbamoyl-2-phenylethenesulfonamide,which is also known as styrenesulfonylurea.

2. Description of the Prior Art

Arenesulfonamides, substituted on the nitrogen atom by a monosubstitutedcarbamoyl group (arenesulfonylureas), are a well-known class of organiccompounds, some of which are known to have hypoglycemic properties. Forexample, N-(N-n-propylcarbamoyl)-p-chlorobenzenesulfonamide(chlorpropamide) and N-(N-n-butylcarbamoyl)-p-toluenesulfonamide(tolbutamide) are clinically-useful oral antidiabetic agents. However,there is a paucity of references in the literature to sulfonylureas inwhich the nitrogen atom of the urea moiety remote from the sulfonylgroup carries two substituents other than hydrogen.

2-Phenylethenesulfonamides, substituted on the nitrogen atom by acarbamoyl group (styrenesulfonylureas), are not well known in thechemical or patent literature, although U.S. Pat. No. 2,979,437, issuedApr. 11, 1961, discloses a series of aralkenesulfonylureas withhypoglycemic properties.

SUMMARY OF THE INVENTION

It is an object of this invention to provide a new method for reducingelevated plasma lipid levels in mammals. The method comprisesadministering to a hyperlipidemic mammal an effective amount of acompound selected from 2-phenylethenesulfonamide derivatives of theformulae: ##SPC1##

And the pharmaceutically-acceptable salts thereof;

WHEREIN X is selected from the group consisting of hydrogen, fluoro,chloro, bromo, trifluoromethyl, alkyl having from one to four carbonatoms and alkoxy having from one to four carbon atoms;

A and B are each selected from the group consisting of hydrogen, methyl,ethyl and phenyl;

Z is selected from the group consisting of pyrrolidino, morpholino,thiomorpholino, 1,2,5,6-tetrahydropyridino,1,2,3,4-tetrahydroisoquinolino, azacycloheptan-1-yl, azacyclooctan-1-yl,3-azabicyclo[3.2.2]nonan-3-yl, piperidino, 4-hydroxypiperidino,4-methoxy piperidino, 4-carboxypiperidino, 4-phenylpiperidino,alkylpiperidino having from one to three carbon atoms in said alkylgroup, (phenylalkyl)piperidino having from one to five carbon atoms insaid alkyl group and ([substituted phenyl]alkyl)piperidino having fromone to five carbon atoms in said alkyl group, said substituted phenylbeing substituted by a moiety selected from the group consisting ofhydroxy, alkyl having from one to four carbon atoms and alkoxy havingfrom one to four carbon atoms;

and R¹ and R² are each selected from the group consisting of hydrogen,alkyl having from one to ten carbon atoms, alkenyl having from three tosix carbon atoms, cycloalkyl having from three to seven carbon atoms,phenylalkyl having from one to two carbon atoms in said alkyl group,carboxyalkyl having from one to seven carbon atoms in said alkyl group,alkoxycarbonylalkyl having from one to two carbon atoms in said alkoxygroup and having from one to seven carbon atoms in said alkyl group,bicyclo[2.2.1]hept-2-en-5-ylmethyl,7-oxabicyclo[2.2.1]heptan-2-ylmethyl, bicyclo[2.2.1]heptan-2-ylmethyl,phenyl and phenyl substituted by a moiety selected from the groupconsisting of fluoro, chloro, bromo, nitro, alkyl having from one tofour carbon atoms and alkoxy having from one to four carbon atoms;provided that R¹ and R² are not both hydrogen.

However, the preferred hypolipidemic agents of this invention are thecompounds of formulae I and II, wherein X is selected from the groupconsisting of hydrogen, chloro and methyl; A and B are each selectedfrom the group consisting of hydrogen, methyl and ethyl; and Z, R¹ andR² are as defined hereinbefore.

Particularly preferred hypolipidemic agents of this invention of formulaI are those compounds of formula I, wherein X is selected from the groupconsisting of hydrogen, chloro and methyl, A and B are each hydrogen andZ is selected from the group consisting of 4-(ω-phenylalkyl)-piperidinohaving from one to five carbon atoms in said alkyl group and4-(ω-[substituted phenyl]alkyl)-piperidino having from one to fivecarbon atoms in said alkyl group, said substituted phenyl beingsubstituted by a moiety selected from the group consisting of hydroxy,alkyl having from one to four carbon atoms and alkoxy having from one tofour carbon atoms. In this context, the terms ω-phenylalkyl andω-[substituted phenyl]alkyl are intended to refer to straight-chainalkyl groups with a phenyl or a substituted phenyl group, respectively,on the terminal carbon atom of the alkyl group, e.g. 2-phenylethyl,3-phenylpropyl and 5-phenylpentyl. The preferred value for X ishydrogen. Expecially valuable compounds of formula I are those compoundswherein X, A and B are each hydrogen and Z is the said4-(ω-phenylalkyl)piperidino.

Other particularly preferred hypolipidemic agents of formula I are thosecompounds of formula I, wherein X is selected from the group consistingof hydrogen, chloro and methyl, A and B are each hydrogen and Z is1,2,3,4-tetrahydroisoquinolino.

Particularly preferred hypolipidemic agents of formula II are thosecompounds of formula II, wherein X, A, B and R¹ are hydrogen and R² iseither the said alkyl, expecially n-butyl, or the said carboxyalkyl,especially carboxymethyl.

Other particularly preferred hypolipidemic agents of formula II, arethose compounds of formula II, wherein X, A and B are each hydrogen andR¹ and R² are each the said alkyl, especially n-butyl.

Individual compounds of the instant invention which are of particularvalue are:

N-(n-n-butylcarbamoyl)-2-phenylethenesulfonamide,

N-(n-[carboxymethyl]carbamoyl)-2-phenylethenesulfonamide,

N-(4-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenylethenesulfonamide.

Many of the hypolipidemic agents of this invention are novel, and assuch they form an important embodiment of the invention. Thus, all thecompounds of formula I are novel. The compounds of formula II are novelprovided that when either R¹ or R² is hydrogen, the said alkyl, the saidalkenyl, the said cycloalkyl, phenyl or the said substituted phenyl, theother R¹ or R² is other than hydrogen or the said alkyl.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the invention, the compounds of formulae I and II areconveniently synthesized from an alkenesulfonamide of formula III,wherein X, A and B are as previously defined, by one of several methods.Five such methods, designated hereinafter as Methods A, B, C, D and E,are now to be discussed and described in detail. ##SPC2##

Method A comprises the reaction of a compound of formula III with anorganic isocyanate of formula R¹ --N=C=O, in the presence of a base. Thereaction is usually carried out by contacting the reagents in anappropriate solvent, at a temperature normally in the range from about25° to about 120°C, and preferably from about 60° to about 80°C.Appropriate solvents which can be used are those which will serve todissolve at least one of the reactants and which do not adverselyinteract with either the reactants or the product. Examples of suchsolvents are ethers, such as diethyl ether, tetrahydrofuran1,2-dimethoxyethane; chlorinated hydrocarbons, such as chloroform,methylene chloride and 1,2-dichloroethane; lower aliphatic ketones, suchas acetone, methyl ethyl ketone and methyl isobutyl ketone; esters, suchas ethyl acetate and butyl acetate; and tertiary amides, such asN,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone. Awide variety of bases, belonging to both the organic and inorganic typescan be used in this process, since it appears that the primary functionof the basic agent is to form a salt of the sulfonamide reactant. Baseswhich are used include tertiary amines, such as triethylamine,tributylamine, N,N-dimethylaniline, pyridine, quinoline,N-methylmorpholine and 1,5-diazabicyclo[4.3.0]non-5-ene; alkali metalhydroxides, such as sodium hydroxide and potassium hydroxide; alkalimetal alkoxides, such as sodium methoxide, potassium methoxide andsodium ethoxide; metal hydrides such as sodium hydride and calciumhydride; metal carbonates, such as sodium carbonate and potassiumcarbonate; and alkali metals such as sodium and potassium. In mostinstances one molar equivalent of base, based on the sulfonamide used,is employed, but amounts smaller or larger than one molar equivalent cansuccessfully be used. Although it is common to aid a one-to two-foldexcess of isocyanate, this is not essential, and equimolar proportionsare sometimes used, particularly in those cases where it would beinconvenient to remove the excess of isocyanate from the product. Infact, it is possible to employ an excess of sulfonamide; in which casesome sulfonamide remains at the end of the reaction. When working atabout 80°C., reaction times of a few hours, for example 2 hours, areusually used. A particularly convenient means of isolating the productinvolves adding the reaction mixture to an excess of dilute aqueousacid. If this causes the product to precipitate, it is filtered offdirectly. Alternatively it is extracted into a water-immiscible organicsolvent, which is then separated off and evaporated, leaving the crudeproduct. In many cases the crude product is essentially pure, but, ifdesired, it can be purified further by methods known in the art.

As will be appreciated by one skilled in the art, it is possible topre-form a salt of the starting sulfonamide, which is then treated withthe isocyanate in a subsequent step. In this case the same method andconditions discussed above are operative in the second step of thistwo-step process.

The starting isocyanates used in Method A are either items of commerce,or they are readily prepared by reaction of the appropriate amine withphosgene, using the method taught by Shriner, Horne and Cox in OrganicSynthesis, Collective Volume II, 453 (1943).

Method B comprises the reaction of a compound of formula III with acarbamoyl chloride of formula Z--C(=O)--Cl or R¹ R² N--C(=O)--Cl, in thepresence of a base. In a typical procedure, approximately one molarequivalent of the carbamoyl chloride is added to a solution orsuspension of the sulfonamide of formula III in an appropriate solvent,in the presence of the base. The same solvents and bases enumeratedabove under Method A are operative in this process, and approximatelyone molar equivalent is commonly employed. On the other hand, largeramounts of base can be used in those cases wherein the excess of basewill not adversely affect the reactants or products. Indeed, an excessis commonly used when the base is not soluble in the reaction medium.The reaction temperature and reaction time vary according to a varietyof factors, such as the reactivity and concentrations of the reagentsand the solubility of the reagents in the particular solvent systemchosen. However, the reaction is usually carried out in the temperaturerange from about 40° to 120°C., and preferably from about 50° to about80°C. At the latter temperatures, reaction times of a few hours, forexample 4 hours, are typically used. The product can be isolated usingthe methods discussed above under Method A.

An alternate variation for Method B, which approximates theSchotten-Baumann procedure, and which is convenient in certaininstances, comprises adding the carbamoyl chloride to a solution of thesulfonamide in water, at about ambient temperature, with the pH beingmaintained within the range from about 7.0 to about 12.0 during andafter the addition. At the end of the reaction, which typically requiresabout one hour, the reaction mixture is acidified. If the productprecipitates it is filtered off. Alternatively it can be extracted intoa water-immiscible organic solvent, which is then separated off, andevaporated, leaving the crude product.

The carbamoyl chlorides used in Method B are either items of commerce,or they are readily prepared by reaction of the appropriate amine withphosgene, using methods discussed by Peterson in Houben-Weyl's "Methodender Organischen Chemie," 8, 115-118 (1962).

In method C, a sulfonamide of formula III reacts with a urea derivativeof formula R¹ NH--CO--NR³ R⁴, in the presence of a base, wherein R³ isselected from the group consisting of alkyl having from one to sixcarbon atoms, alkenyl having from three to seven carbon atoms, aryl,substituted aryl, heteroaryl and substituted heteroaryl, and R⁴ isselected from the group consisting of hydrogen, cycloalkyl having fromthree to eight carbon atoms, benzyl, phenylethyl and R³, wherein eachsubstituted moiety is substituted by up to three members selected fromthe group consisting of chloro, fluoro, bromo, nitro, alkyl having fromone to four carbon atoms and alkoxy having from one to four carbonatoms. Typical examples of aryl groups are phenyl and naphthyl, andtypical examples of heteroaryl groups are pyridyl, thiazolyl, oxazolyland quinolyl. A particularly convenient configuration for the ureamoiety used in this Method is that wherein R³ and R⁴ are each phenyl.The reaction is carried out by contacting sulfonamide and urea usingexactly the same solvents, reaction parameters, bases and reactantratios, etc., described hereinbefore for the operation of Method A.Indeed it is postulated that, under the influence of base, the urea offormula R¹ NH--CO--NR³ R⁴ acts as a source of isocyanate. However, thisis a matter of theory, and in no way affects the conduct of thereaction.

The substituted ureas of formula R¹ NH--CO--NR³ R⁴ are prepared from theappropriate amine of formula R¹ NH₂ and carbamoyl chloride of formulaCl--CO--NR² R⁴, using the procedure of McManus et al. (Journal ofMedicinal Chemistry, 8, 766 ([1965]) and minor variations thereof. Thecarbamoyl chlorides of formula Cl--CO--NR³ R⁴ are obtained from theappropriate amine of formula HNR³ R⁴ and phosgene as indicated in MethodB.

Method D comprises the reaction of a sulfonyl isocyanate of formula IV,wherein X, A and B are as defined previously, with the appropriate amineof formula HZ or HNR¹ R². The reaction is usually carried out bycontacting the isocyanate and amine in a reaction-inert, organicsolvent, at or about ambient temperature, until the reaction issubstantially complete. Reaction times of a few hours, e.g. from about 1hour to about 12 hours, are commonly used. The same solvents enumeratedin method A are useful in the instant process, and the product isrecovered by methods discussed above under Method A. Although the ratioof isocyanate to amine is not critical, and use of an excess of eithercomponent will successfully lead to product, it is usual to employ asmall excess of amine, for example a one-fold excess.

The starting sulfonyl isocyanates are prepared from the correspondingsulfonamide of formula III, by reaction with an excess of oxalylchloride, followed by pyrolysis of the oxamic acid chloride intermediatethus obtained. Such transformations are well-known in the art. See, forexample, Franz and Osuch, Journal of Organic Chemistry, 29, 2592 (1964).It is a convenient procedure in many instances to use the sulfonylisocyanate in the solvent in which it is prepared, without isolation.Moreover, if desired, the oxamic acid chloride can be treated directlywith the amine, and this will successfully lead to the formation of acompound of formula I or II. ##SPC3##

Method E comprises the reaction of an amine of formula HZ or HNR¹ R²with a compound of formula V, wherein Z, R¹, R², R³ and R⁴ are asdefined previously. The reaction is usually conducted by heating the tworeactants together ##SPC4##

in a reaction-inert organic solvent, which is usually a polar, organicsolvent which serves to dissolve the reactants. Appropriate solventsare, for example, lower alkanols, such as methanol, ethanol andn-butanol; glycols, such as ethylene glycol and propylene glycol;ethers, such as dioxane and 1,2-dimethoxyethane; acetonitrile; andtertiary amides, such as N,N-dimethylformamide, N,N-dimethylacetamideand N-methylpyrrolidone. The temperature and duration of reactionrequired to complete the conversion to product are interrelated. Atlower temperatures longer periods are required, while at highertemperatures the reaction is complete in a shorter time. Moreover, therate of reaction depends on the nucleophilicity of the reactant amineand the efficacy of the leaving group. In any event, reaction times of afew hours are usually used, and the reaction is normally conducted inthe range from about 50° to about 150°C and preferably in the range fromabout 80° to 100°C. At around 100°C. a reaction time of about 5 hours iscommonly used. If desired, the starting compound of formula V can beused in the form of a salt, for example an alkali metal salt, such as apotassium salt. Alternatively, the compound of formula V can beintroduced into the reaction medium in the form of a salt, which is thenneutralized by the addition of an alkanoic acid, such as acetic acid.Although the reactants in this Method are normally combined in equimolarproportions, the ratio of reactant is not critical and an excess ofeither component can successfully be used. The product can be isolatedby evaporating the solvent in vacuo, and then partitioning the residuebetween dilute aqueous acid and a water-immiscible organic solvent.Evaporation of the organic solvent then affords the crude product, whichcan be purified further by well-known methods, if desired.

In certain instances, Method D is carried out in the absence of asolvent. In this case the sulfonamide of formula V and the amine aresimply heated together, until the conversion to product is substantiallycomplete. As indicated above, reaction times of a few hours, e.g. about5 hours are used, and the reaction is usually conducted at a temperaturein the range from about 50° to about 150°C., and preferably in the rangefrom about 80° to about 100°C. This particular variation is convenientwhen the compound of formula V and the amine exist in the liquid phaseat the reaction temperature.

Although the detailed course of Method D has not been elucidated, it ishypothesized that some sulfonyl isocyanate of formula IV is generated insitu during the course of the reaction.

Preferred values for R³ are alkyl having from one to six carbon atoms,phenyl and phenyl substituted by up to two moieties selected from thegroup consisting of fluoro, chloro, bromo, nitro, alkyl having from oneto four carbon atoms and alkoxy having from one to four carbon atoms,and preferred values for R⁴ are hydrogen and R³. Particularly preferredstarting materials of formula V, are those wherein R³ and R⁴ are eachphenyl.

The compounds of formula IV are prepared by reaction of the appropriatesulfonamide of formula III with a carbamoyl chloride of formulaCl--CO--NR³ R⁴, using the procedure discussed under Method B.

As will be appreciated by one skilled in the art, not all of the MethodsA, B, C, and D are equally applicable to the synthesis of all thecompounds of formulae I and II. For example, Methods A and C aresuitable only for preparing compounds of formula II, wherein either R¹or R² is hydrogen. In an individual case, the skilled artist will selectthat synthetic method which is most appropriate, based on such factorsas, for example, the feasibility of the chemical reactions, theavailability of the starting materials, the reactivity of the startingmaterials, the stability of the reagents and products and the scale ofthe reaction to be run.

A further alternate synthetic method which is used specifically forthose compounds of formula II, wherein either R¹ or R² is carboxyalkyl,is the hydrolysis of the corresponding compound of formula II, whereineither R¹ or R² is alkoxycarbonylalkyl. Because of the stabilitycharacteristics of the said compounds of formula II, and ease ofoperation, the instant hydrolysis is usually carried out using basicconditions. In many instances it is sufficient simply to dissolve theester in dilute sodium hydroxide solution, store the solution at ambienttemperature for a few hours, and then acidify the solution. Either theproduct precipitates in a form which can be filtered off, or it isextracted into a water-immiscible solvent such as ethyl acetate. Thesolvent is then dried and evaporated in order to recover the crudeproduct. However, a variety of water-miscible co-solvents, such as loweralkanols, for example methanol and ethanol, or acetone, can be added toaid dissolution. Furthermore, various other bases known in the art to beuseful for alkaline hydrolysis reactions, such as, for example,potassium hydroxide, calcium hydroxide, barium hydroxide, sodiumcarbonate and potassium carbonate, are equally operative. The basicagent will normally be present to the extent of at least one molarequivalent based on the ester used, but larger amounts, up to about 20molar equivalents can be used. Although the reaction is commonlyconducted at ambient temperature, it is possible to use temperatures inthe range from about 0° to about 100°C. The time course of the reactionvaries according to the temperature, since the reaction proceeds morequickly as the reaction temperature is increased. However, when thereaction is carried out at about 25° to 50°C., reaction times of severalhours, for example overnight, are commonly used.

A still further alternate synthetic method is used for preparation ofthe compounds of formula I, wherein Z is([hydroxyphenyl]alkyl)piperidino. The method comprises demethylation ofthe appropriate compound of formula I, wherein Z is the corresponding([methoxyphenyl]alkyl)piperidino. The demethylation is carried out bymethods known in the art for such a transformation, which do notadversely affect the remainder of the molecule. A particular convenientreagent in this regard is boron tribromide, use of which is discussed byFieser and Fieser in "Reagents for Organic Synthesis," John Wiley &Sons, Inc., New York, 1967, page 66.

As discussed hereinbefore, the starting reagents used in Methods A, B,C, D, and E are sulfonamides of formula III. These sulfonamides can beprepared from ethene derivatives of formula VI, by either of twomethods. The first of these comprises the following sequence ofreactions: ##SPC5##

The reagents and conditions used in this sequence are those described,with minor variations, by Bordwell et al. (Journal of the AmericanChemical Society, 68, 139 [1946]) for the case wherein A, B, and X areeach hydrogen. Operation of this reaction sequence is furtherexemplified in U.S. Pat. No. 2,979,437. The second method used for theconversion of the ethene derivatives of formula VI into thecorresponding sulfonamides of formula III, comprises treatment of thesaid ethene derivatives with sulfuryl chloride in N,N-dimethylformamide,followed by ammonia, using the conditions of Culbertson and Dietz(Journal of the Chemical Society [London], Part C, 992 [1968]), andminor variations thereof.

The ethene derivatives of formula VI are either items of commerce, orthey are prepared by either of two general methods, both well-known inthe art. The first method comprises a Wittig between a carbonyl compoundof formula VII, and the ylid derived from a phosphonium salt of formula([C₆ H₅ ]₃ PCH₂ B)^(+Y) ⁻, wherein Y is chloride or bromide as discussedand described by Maercker in "Organic Reactions," 14, 270 (1965), and byDeno et al., in the Journal of the American Chemical Society, 87, 2157(1965). ##SPC6##

The second method comprises reaction of a carbonyl compound of formulaVII with a Grignard reagent of formula BCH₂ MgY, wherein Y is chlorideor bromide, followed by acid-catalysed dehydration of the carbinol soproduced, in accordance with procedures discussed by Emerson in ChemicalReviews, 45, 347 (1949), viz: ##SPC7##

Choice between these two methods will normally be made by the skilledartist on the basis of such factors as the availability of the startingmaterials, the ease of operation of the method on the scale of reactioncontemplated, and the reactivity of the particular reactants.

The carbonyl compounds of formula VII are either items of commerce, orthey are prepared by the published literature method. The phosphoniumsalts of formula ([C₆ H₅ ]₃ PCH₂ B)^(+Y) ⁻, are conveniently preparedfrom triphenylphosphine and the appropriate alkyl halide, in accordancewith procedures discussed by Maercker, loc. cit., pp 338-393. The alkylhalides are all commercially available.

As will be appreciated by one skilled in the art, many of thealkenesulfonamides of formula II are useful not only as hypolipidemicagents, but also as intermediates for the preparation of hypolipidemicagents. Thus, the compounds of formula II, wherein either R¹ or R² isselected from the group consisting of phenyl and phenyl substituted by amoiety selected from the group consisting of fluoro, chloro, bromo,nitro, alkyl having from one to four carbon atoms and alkoxy having fromone to four carbon atoms, are useful as starting materials for Method E,described hereinbefore. Moreover, the compounds of formula II, whereineither R¹ or R² is alkoxycarbonylalkyl, are valuable as startingmaterials for the preparation by hydrolysis, of the correspondingcompounds of formula II, wherein either R¹ or R² is carboxyalkyl.

The hypolipidemic properties of the compounds of the instant inventionare readily demonstrated by either of two methods. In the first method,which is essentially the method used by Newman et al. (Lipids, 8, 378[1973]), the ability of the compounds to inhibit Triton-inducedhyperlipidemia in rats is demonstrated. A 300-mg./kg. dose of TritonWR-1339 is injected into normal, Sprague-Dawley, male rats which havebeen treated orally with the test compound. After further oral dosagewith the test compound, the rats are exsanguinated via the abdominalaorta under pentobarbital anesthesia and plasma is obtained from theheparinized blood. Plasma cholesterol concentration is measured usingthe Auto-Analyser (Technicon Method N-24a), and the value is comparedwith that obtained from control animals which have received the Tritontreatment but no test compound. The plasma cholesterol level in thetest-compound fed animals is found to be significantly lower whencompared to the levels in animals not receiving the test compound.

In the second method for measuring hypolipidemic properties of thecompounds of the instant invention, normal adult, beagle dogs are dosedorally, twice daily, with the test compound, for a period of six days.During the period of the test, the dogs are fed once daily, at 12:00noon. On the morning of the sixth day, the dogs are bled from thejugular vein and plasma cholesterol is measured by the method adaptedfor use in the Technicon Auto-Analyser. The level obtained in a givendog is compared with the baseline value for the dog, which has beendetermined at the start of the test. The plasma cholesterol level isfound to be significantly lower at the end of the test, when compared tothe baseline value obtained at the beginning of the test.

A characteristic feature of the compounds of the instant invention istheir ability to form salts. By virtue of their acidic nature,sulfonylureas have the ability to form salts with basic agents, and allsaid salts are to be considered a further embodiment of the invention.The salts can be prepared readily and conveniently, for example, simplyby contacting the acidic and basic entities, usually in a 1:1 molarratio, in either an aqueous, non-aqueous or partially aqueous medium, asappropriate. The salts are recovered either by filtration, byprecipitation with a non-solvent, by evaporation of the solvent, asappropriate, or, in the case of aqueous solutions, by lyophilization.

Basic agents suitably employed in salt formation belong to both theorganic and inorganic types, and they include ammonia, organic amines,alkali metal hydroxides, alkali metal carbonates, alkali metalbicarbonates, alkali metal hydrides, alkali metal alkoxides, alkalineearth metal hydroxides, alkaline earth metal carbonates, alkaline earthmetal hydrides and alkaline earth metal alkoxides. Representativeexamples of such bases are primary amines, such as n-propylamine,n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine andoctylamine; secondary amines, such as diethylamine, N-methylaniline,morpholine, pyrrolidine and piperidine; tertiary animes, such astriethylamine, N,N-dimethylaniline, N-ethylpiperidine,N-methylmorpholine and 1,5-diazobicyclo[4.3.0]non-5-ene; hydroxides,such as sodium hydroxide; alkoxides, such as sodium ethoxide andpotassium ethoxide; hydrides, such as calcium hydride and sodiumhydride; carbonates, such as potassium carbonate and sodium carbonate;and bicarbonates, such as sodium bicarbonate and potassium bicarbonate.

As will be appreciated by one skilled in the art, the compounds offormula II, wherein either R¹ or R² is carboxyalkyl have the furtherability to form carboxylate salts. These salts, which can be formed inexactly the same manner and using exactly the same basic agents, asdescribed above, are also within the purview of the instant invention.In the cases wherein a compound of formula II has two acidic groups,both mono- and di-salts can be prepared. When considering di-salts, thetwo cationic species can be the same or different.

Although, when contemplating therapeutic use for a compound of theinstant invention it is preferable to use a pharmaceutically-acceptablesalt, salts other than these can be used for a variety of otherpurposes. Such purposes include isolating and purifying particularcompounds, and interconverting pharmaceutically-acceptable salts withtheir non-salt counterparts.

The hypolipidemic properties of the alkenesulfonamides of the instantinvention make them particularly suitable and valuable for the controlof hyperlipidemia in mammals, especially man. For therapeutic use of acompound of this invention, the compound can be administered alone, or,preferably, it can be mixed with pharmaceutically-acceptable carriers ordiluents. Said carrier or diluent is chosen on the basis of the intendedmode of administration, as well as the solubility and stability of theactive ingredient. For example, when considering the oral mode ofadministration, a hypolipidemic alkenesulfonamide of this invention canbe used in the form of tablets, capsules, lozenges, troches, powders,syrups, elixiers, aqueous solutions and suspensions, and the like, inaccordance with standard pharmaceutical practice. The proportional ratioof active ingredient to carrier will naturally depend on the chemicalnature, solubility and stability of the active ingredient, as well asthe dosage contemplated. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch, and lubricatingagents, such as sterotex K, are commonly added. For oral administrationin capsule form, useful diluents are lactose and dried corn starch. Whenaqueous suspensions are required for oral use, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening and/or flavoring agents can be added. For parenteraladministration, which includes intramuscular, intraperitoneal,subcutaneous and intravenous use, sterile solutions of the activeingredient are usually prepared, and the pH of the solutions should besuitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled to render the preparationisotonic.

When the hypolipidemic compounds of this invention are used for thecontrol, that is cure or prophylaxis, of hyperlipidemia in man, thedaily dosages will normally be determined by the prescribing physician.Moreover, these dosages will vary according to the age, weight andresponse of the individual patient, as well as the severity of thepatient's symptoms. However, in most instances, an effective dailydosage will be in the range from about 0.5 g. to about 3.0 g., in singleor divided doses. On the other hand, it may be necessary to use dosagesoutside these limits in some cases.

The following examples are provided solely for the purpose of furtherillustration.

EXAMPLE I N-(N-Butylcarbamoyl)-1-phenylpropene-2-sulfonamide

To a mixture of 80 ml. of triethylamine and 50 ml. ofN,N-dimethylformamide, is added 39.5 g. of 1-phenylpropene-2-sulfonamidefollowed by 32.5 ml. of n-butyl isocyanate. The mixture is heated at85°-90°C., with stirring, for 75 minutes. It is cooled to ambienttemperature, and then it is poured with stirring into 1 liter of 20%acetic acid. After a further 30 minutes of stirring, the precipitatewhich forms is filtered off and then dissolved in 300 ml. of hotacetone. The acetone is filtered, and then allowed to cool slowly. Thecrude product which precipitates is filtered off, washed with aqueousacetone, and allowed to dry. The acetone mother liquors are diluted withwater, which causes a second crop of product to precipitate. It isfiltered off. The crops are combined and then recrystallized fromethanol, giving 28 g. ofN-(N-butylcarbamoyl)-1-phenylpropene-2-sulfonamide, m.p. 135°-136° C.

Analysis--Calcd. for C₁₄ H₂₀ N₂ O₃ S (percent): C, 56.74; H, 6.80; N,9.45. Found: (percent): C, 56.64; H, 6.78; N, 9.27.

EXAMPLE II

Following the procedure of Example I, and reacting either1-phenylpropene-2-sulfonamide, 2-phenylpropene-1-sulfonamide or2,2-diphenylethenesulfonamide with the appropriate isocyanate, thefollowing compounds are prepared: ##SPC8##

    __________________________________________________________________________                                  Analysis                                                                      Calc'd (%)   Found (%)                           A    B    Z           m.p. (°C.)                                                                    C    H   N   C    H    N                        __________________________________________________________________________    hydrogen                                                                           methyl                                                                             N-isopropylamino                                                                           191-192                                                                              55.31                                                                              6.43                                                                              9.92                                                                              55.48                                                                              6.39 9.65                     hydrogen                                                                           methyl                                                                             N-propylamino                                                                              190-192                                                                              55.31                                                                              6.43                                                                              9.92                                                                              55.61                                                                              6.51 10.19                    hydrogen                                                                           methyl                                                                             N-heptadecylamino                                                                          118.5-122                                                                            68.26                                                                              9.82                                                                              5.69                                                                              68.18                                                                              10.12                                                                              5.66                     methyl                                                                             hydrogen                                                                           N-propylamino                                                                              176-178                                                                              55.31                                                                              6.43                                                                              9.92                                                                              55.22                                                                              6.40 9.84                     methyl                                                                             hydrogen                                                                           N-cyclohexylamino                                                                          155-158                                                                              59.60                                                                              6.88                                                                              8.69                                                                              59.91                                                                              7.21 8.62                     hydrogen                                                                           methyl                                                                             N-cyclohexylamino                                                                          142-146                                                                              59.60                                                                              6.88                                                                              8.69                                                                              59.52                                                                              7.01 8.79                     methyl                                                                             hydrogen                                                                           N-isopropylamino                                                                           163-165                                                                              55.31                                                                              6.43                                                                              9.92                                                                              55.23                                                                              6.32 9.81                     hydrogen                                                                           methyl                                                                             N-(m-tolyl)amino                                                                           137-139                                                                              61.81                                                                              5.49                                                                              8.48                                                                              61.94                                                                              5.49 8.34                     methyl                                                                             hydrogen                                                                           N-propylamino                                                                              103-105                                                                              56.73                                                                              6.80                                                                              9.45                                                                              56.53                                                                              6.98 9.69                     hydrogen                                                                           hydrogen                                                                           N-(ethoxycarbonyl-                                                            methyl)amino 172-174                                                                              50.00                                                                              5.16                                                                              8.97                                                                              50.12                                                                              5.13 9.02                     hydrogen                                                                           hydrogen                                                                           N-(1-adamantyl)amino                                                                       186-187.5                                                                            63.32                                                                              6.71                                                                              7.77                                                                              63.29                                                                              6.81 7.67                     hydrogen                                                                           methyl                                                                             N-(tert-butyl)amino                                                                        181-182                                                                              56.74                                                                              6.80                                                                              9.45                                                                              56.48                                                                              6.85 9.49                     hydrogen                                                                           methyl                                                                             N-(1-adamantyl)amino                                                                       168-170                                                                              64.15                                                                              7.00                                                                              7.48                                                                              64.23                                                                              6.86 7.50                     hydrogen                                                                           methyl                                                                             N-(ethoxycarbonyl-                                                            methyl)amino 181-182                                                                              51.23                                                                              5.56                                                                              8.59                                                                              51.61                                                                              5.59 8.56                     hydrogen                                                                           hydrogen                                                                           N-(1-methoxycarbonyl-                                                         2-phenylethyl)amino                                                                        168-170                                                                              51.88                                                                              5.99                                                                              7.56                                                                              51.76                                                                              5.90 7.57                     hydrogen                                                                           hydrogen                                                                           N-(1-methoxycarbonyl-                                                         3-methylbut-1-yl)amino                                                                     156-158                                                                              54.23                                                                              6.26                                                                              7.91                                                                              54.12                                                                              6.25 7.94                     phenyl                                                                             hydrogen                                                                           N-isopropylamino                                                                           209-210                                                                              62.78                                                                              5.85                                                                              8.14                                                                              62.44                                                                              5.94 8.14                     phenyl                                                                             hydrogen                                                                           N-propylamino                                                                              184-186                                                                              62.78                                                                              5.85                                                                              8.14                                                                              62.56                                                                              5.89 8.00                     __________________________________________________________________________

EXAMPLE III

When methyl isocyanate, ethyl isocyanate, isobutyl isocyanate, n-hexylisocyanate, n-heptyl isocyanate, n-decyl isocyanate, allyl isocyanate,3,3-dimethylbut-2-yl isocyanate, cyclopropyl isocyanate, cyclopentylisocyanate, cyclohexyl isocyanate, cycloheptyl isocyanate, phenylisocyanate, p-fluorophenyl isocyanate, m-bromophenyl isocyanate,m-nitrophenyl isocyanate, p-tolyl isocyanate, p-ethylphenyl isocyanate,p-chlorophenyl isocyanate, o-chlorophenyl isocyanate, p-methoxyphenylisocyanate, m-ethoxyphenyl isocyanate, p-butoxyphenyl isocyanate,m-methoxyphenyl isocyanate, benzyl isocyanate, 1-phenylethyl isocyanate,2-phenylethyl isocyanate, ethoxycarbonylmethyl isocyanate andmethoxycarbonylmethyl isocyanate, respectively, reacts with2-phenylbut-1-ene-2-sulfonamide,2-(p-chlorophenyl)propene-1-sulfonamide,2-(p-methoxyphenyl)propene-1-sulfonamide,1-(m-chlorophenyl)propene-2-sulfonamide,2-(p-chlorophenyl)but-1-ene-1-sulfonamide,1,2-diphenylethenesulfonamide, 3-phenylbut-2-ene-2-sulfonamide,1-(p-chlorophenyl)propene-2-sulfonamide, 1-phenylpropene-2-sulfonamide,1,2-diphenylpropene-1-sulfonamide,1-(p-chlorophenyl)propene-2-sulfonamide,2-(p-tolyl)propene-1-sulfonamide,2-(p-isopropylphenyl)propene-1-sulfonamide,1-(p-ethoxyphenyl)propene-2-sulfonamide, 2-phenylpropene-1-sulfonamide,2-(p-fluorophenyl)propene- 1-sulfonamide, 2,2-diphenylethenesulfonamide,2-(p-butoxyphenyl)propene- 1-sulfonamide,2-(p-tolyl)propene-1-sulfonamide, 1-phenylbut-1-ene-2-sulfonamide,3(m-chlorophenyl)but-2-ene-2-sulfonamide,2-(p-chlorophenyl)-2-phenylethenesulfonamide,2-(p-chlorophenyl)propene-1-sulfonamide,2-(p-n-butylphenyl)propene-1-sulfonamide, 2-phenylpropene-1-sulfonamide,1-phenylpropene-2-sulfonamide, 2-(m-methoxyphenyl)propene-1-sulfonamideand 2-(p-biphenylyl)propene-1-sulfonamide, respectively, according tothe procedure of Example I, the following compounds are produced:

N-(n-methylcarbamoyl)-2-phenylbut-1-ene-1-sulfonamide,

N-(n-ethylcarbamoyl)-2-(p-chlorophenyl)propene-1-sulfonamide,

N-(n-isobutylcarbamoyl)-2-(p-methoxyphenyl)propene-1-sulfonamide,

N-(n-n-hexylcarbamoyl)-1(m-chlorophenyl)propene-2-sulfonamide,

N-(n-n-heptylcarbamoyl)-2-(p-chlorophenyl)but-1-ene-1-sulfonamide,

N-(n-decylcarbamoyl)-1,2-diphenylethenesulfonamide,

N-n-allylcarbamoyl)-2-phenylbut-2-ene-2-sulfonamide,

N-(n-[3,3-dimethylbut-2-yl]carbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

N-(n-cyclopropylcarbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n-cyclopentylcarbamoyl)-1,2-diphenylpropene-1-sulfonamide,

N-(n-cyclohexylcarbamoyl)-1(p-chlorophenyl)propene-2-sulfonamide,

N-(n-cyclopheptylcarbamoyl)-2-(p-tolyl)propene-1-sulfonamide,

N-(n-phenylcarbamoyl)-2-(p-isopropylphenyl)propene-1-sulfonamide,

N-(n-p-fluorophenylcarbamoyl)-1-(p-ethoxyphenyl)propene-2-sulfonamide,

N-(n-m-bromophenylcarbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-m-nitrophenylcarbamoyl)-2-(p-fluorophenyl)propene-1-sulfonamide,

N-(n-p-tolylcarbamoyl)-2,2-diphenylethenesulfonamide,

N-(n-p-ethylphenylcarbamoyl)-2-(p-butoxyphenyl)propene-1-sulfonamide,

N-(n-p-chlorophenylcarbamoyl)-2-(p-tolyl)propene-1-sulfonamide,

N-(n-p-chlorophenylcarbamoyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(n-p-methoxyphenylcarbamoyl)-3-(m-chlorophenyl)but-2-ene-2-sulfonamide,

N-(n-m-ethoxyphenylcarbamoyl)-2-(p-chlorophenyl)-2-phenylethenesulfonamide,

N-(n-p-butoxyphenylcarbamoyl)-2-(p-chlorophenyl)propene-1-sulfonamide,

N-(n-m-methoxyphenylcarbamoyl)-2-(p-n-butylphenyl)propene-1-sulfonamide,

N-(n-benzylcarbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[1-phenylethyl]carbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[2-phenylethyl]carbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n-[ethoxycarbonylmethyl]carbamoyl)-2-(m-methoxyphenyl)propene-1-sulfonamideand

N-(n-[methoxycarbonylmethyl]carbamoyl)-2-(p-biphenylyl)propene-1-sulfonamide,respectively,

EXAMPLE IV N-(N,N-Diphenylcarbamoyl)-2-phenylethenesulfonamide

To a suspension of 35g. of potassium carbonate in 500 ml. of acetone isadded 18.3g. of 2-phenylethenesulfonamide and 35g. ofN,N-diphenylcarbamoyl chloride. The reaction mixture is heated underreflux with stirring for 51/2 hours. The insoluble materials arefiltered from the hot acetone, and then the acetone is concentrated todryness in vacuo. The residue is slurried in 300 ml. of ether and thenfiltered off. This gives 43g. of the potassium salt of the product.

The potassium salt is dissolved in a mixture of 200ml. of acetone and 50ml. of water. The solution is acidified using concentrated hydrochloricacid, and then a further 50ml. of water is added. The solid whichprecipitates is filtered off, and washed successively with acetone-water(1:1) and then with water. This gives 33g. (87%) ofN-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide, m.p. 185°-188°C.Recrystallization of the product raises the melting point to 189°-191°C.

Analysis--Calcd. for C₂₁ H₁₈ N₂ O₃ S (percent): C, 66.66; H, 4.80; N,7.40. Found (percent): C, 66.46; H, 4.82; N, 7.17.

EXAMPLE V

When the procedure of Example IV is repeated, except that theN,N-diphenylcarbamoyl chloride used therein is replaced by an equimolaramount of N,N-dimethylcarbamoyl chloride, there is producedN-(N,N-dimethylcarbamoyl)-2-phenylethenesulfonamide, m.p. 160°-162° C.

Analysis -- Calc'd for C₁₁ H₁₄ N₂ O₃ S (percent): C, 51.96; H, 5.55, N,11.02. Found (percent): C, 51.88; H, 5.56, N, 11.07.

EXAMPLE VI

The procedure of Example IV is repeated, except that the 2-phenylethenesulfonamide used therein is replaced by an equimolar amount of1-phenylpropene-2-sulfonamide. The product isN-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide, m.p. 175°-179°C.

Analysis -- Calc'd for C₂₂ H₂₀ N₂ O₃ S (percent): C, 67.33; H, 5.14, N,7.14. Found (percent): C, 67.09; H, 5.24, N, 7.11.

EXAMPLE VII

When the procedure of Example IV is repeated, and the2-phenylethenesulfonamide used therein is replaced by an equimolaramount of:

2-(4-biphenyl)ethenesulfonamide,

2-phenylpropene-1-sulfonamide,

2,2-diphenylethenesulfonamide,

1,2-diphenylethenesulfonamide,

2-phenylbut-1-ene-1-sulfonamide,

1-phenylbut-1-ene-2-sulfonamide,

3-phenylbut-2-ene-2-sulfonamide,

2-(m-chlorophenyl)ethenesulfonamide,

2-(o-chlorophenyl)ethenesulfonamide,

2-(p-chlorophenyl)ethenesulfonamide,

2-(p-bromophenyl)ethenesulfonamide,

2-(m-bromophenyl)ethenesulfonamide,

2-(p-fluorophenyl)ethenesulfonamide,

2-(m-tolyl)ethenesulfonamide,

2-(p-ethylphenyl)ethenesulfonamide,

2-(p-tert-butylphenyl)ethenesulfonamide,

2-(o-methoxyphenyl)ethenesulfonamide,

2-(m-isopropoxyphenyl)ethenesulfonamide,

2-(p-butoxyphenyl)ethenesulfonamide,

2-(m-chlorophenyl)propene-1-sulfonamide,

2-(p-chlorophenyl)propene-1-sulfonamide,

2-(m-bromophenyl)propene-1-sulfonamide,

2-(p-fluorophenyl)propene-1-sulfonamide,

2-(m-tolyl)propene-1-sulfonamide,

2-(p-isopropylphenyl)propene-1-sulfonamide,

2-(p-methoxyphenyl)propene-1-sulfonamide,

1-(o-chlorophenyl)propene-2-sulfonamide,

1-(m-chlorophenyl)propene-2-sulfonamide,

1-(p-chlorophenyl)propene-2-sulfonamide,

1-(p-fluorophenyl)propene- 2-sulfonamide,

1-(p-tolyl)propene-2-sulfonamide,

1-(m-methoxyphenyl)propene-2-sulfonamide,

1-(p-ethoxyphenyl)propene-2-sulfonamide,

2-(p-chlorophenyl)but-1-ene-1-sulfonamide,

2-(p-tolyl)but-1-ene-1-sulfonamide,

2-(m-methoxyphenyl)but-1-ene-1-sulfonamide,

1-(p-chlorophenyl)but-1-ene-2-sulfonamide,

1-(m-methoxyphenyl)but-1-ene-2-sulfonamide,

3-(p-chlorophenyl)but-2-ene-2-sulfonamide and

1,2-diphenylpropene-1-sulfonamide,

respectively, this affords:

N-(n,n-diphenylcarbamoyl)-2-(4-biphenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2,2-diphenylethenesulfonamide,

N-(n,n-diphenylcarbamoyl)1,2-diphenylethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-phenylbut-1-ene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-3-phenylbut-2-ene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(m-chlorophenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(o-chlorophenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-bromophenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(m-bromophenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-fluorophenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(m-tolyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-ethylphenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-tert-butylphenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(o-methoxyphenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(m-isopropoxyphenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-butoxyphenyl)ethenesulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(m-chlorophenyl)propene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-chlorophenyl)propene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(m-bromophenyl)propene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-fluorophenyl)propene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(m-tolyl)propene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-isopropylphenyl)propene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-methoxyphenyl)propene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(o-chlorophenyl)propene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(m-chlorophenyl)propene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(p-fluorophenyl)propene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(p-tolyl)propene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(m-methoxyphenyl)propene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(p-ethoxyphenyl)propene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-chlorophenyl)but-1-ene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(p-tolyl)but-1-ene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-2-(m-methoxyphenyl)but-1-ene-1-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(p-chlorophenyl)but-1-ene-2-sulfonamide,

N-(n,n-diphenylcarbamoyl)-1-(m-methoxyphenyl)but-1-ene-2-sulfonamide,

N-(N,N-diphenylcarbamoyl)-3-(p-chlorophenyl)but-2-ene-2-sulfonamide and

N-(n,n-diphenylcarbamoyl)-1,2-diphenylpropene-1-sulfonamide,

respectively.

EXAMPLE VIII

When the procedure of Example IV is repeated, and the alkenesulfonamidecomponent is:

2-phenylethenesulfonamide,

1-phenylpropene-2-sulfonamide,

2-(p-methoxyphenyl)ethenesulfonamide,

2-(m-tolyl)ethenesulfonamide,

2-phenylethenesulfonamide,

1-(p-chlorophenyl)propene-2-sulfonamide,

1-(p-fluorophenyl)propene-2-sulfonamide,

3-phenylbut-2-ene-2-sulfonamide,

2-phenylethenesulfonamide,

2-(o-chlorophenyl)ethenesulfonamide,

2-(m-methoxyphenyl)propene-1-sulfonamide,

2-(p-tolyl)ethenesulfonamide,

2-(p-fluorophenyl)ethenesulfonamide,

2-phenylbut-1-ene-1-sulfonamide,

2-(p-chlorophenyl)ethenesulfonamide,

1-phenylbut-1-ene-2-sulfonamide,

2-(p-isopropoxyphenyl)ethenesulfonamide,

2-(m-chlorophenyl)ethenesulfonamide,

2-phenylethenesulfonamide,

2-(p-chlorophenyl)ethenesulfonamide,

1,2-diphenylethene and

2-phenylethenesulfonamide,

respectively, and the carbamoyl chloride component is:

N-phenyl-N-(p-chlorophenyl)carbamoyl chloride,

N-phenyl-N-(p-chlorophenyl)carbamoyl chloride,

N-phenyl-N-(p-chlorophenyl)carbamoyl chloride,

N-phenyl-N-(p-chlorophenyl)carbamoyl chloride,

N,n-di(p-methoxyphenyl)carbamoyl chloride,

N,n-di(p-methoxyphenyl)carbamoyl chloride,

N-methyl-N-(p-fluorophenyl)carbamoyl chloride,

N-methyl-N-(m-bromophenyl)carbamoyl chloride,

N-ethyl-N-(p-nitrophenyl)carbamoyl chloride,

N-(n-butyl)-N-(p-tolyl)carbamoyl chloride,

N-(n-decyl)-N-(p-ethylphenyl)carbamoyl chloride,

N-methyl-N-(p-tert-butylphenyl)carbamoyl chloride,

N-(n-propyl)-N-(m-isopropoxyphenyl)carbamoyl chloride,

N-(isopropyl)-N-(p-n-butoxyphenyl)carbamoyl chloride,

N-allyl-N-phenylcarbamoyl chloride,

N-benzyl-N-phenylcarbamoyl chloride,

piperidinocarbonyl chloride,

(4-benzylpiperidino)carbonyl chloride,

(4-[3-phenylprop-1-yl]piperidino)carbonyl chloride,

(4-[3-phenylprop-1-yl]piperidino)carbonyl chloride,

morpholinocarbonyl chloride and

(1,2,3,4-tetrahydroquinolino)carbonyl chloride,

respectively, the following compounds are prepared:

N-(n-phenyl-N-[p-chlorophenyl]carbamoyl)-2-phenylethenesulfonamide,

N-(n-phenyl-N-[p-chlorophenyl]carbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n-phenyl-N-[p-chlorophenyl]carbamoyl)-2-(p-methoxyphenyl)ethenesulfonamide,

N-(n-phenyl-N-[p-chlorophenyl]carbamoyl)-2-(m-tolyl)ethenesulfonamide,

N-(n,n-di[p-methoxyphenyl]carbamoyl)-2-phenylethenesulfonamide,

N-(n,n-di[p-methoxyphenyl]carbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

N-(n-methyl-N-[p-fluorophenyl]carbamoyl)-1-(p-fluorophenyl)propene-2-sulfonamide,

N-(n-methyl-N-[m-bromophenyl]carbamoyl)-2-phenylbut-2-ene-2-sulfonamide,

N-(n-ethyl-N-[p-nitrophenyl]carbamoyl)-2-phenylethenesulfonamide,

N-(n-[n-butyl]-N-[p-tolyl)carbamoyl)-2-(o-chlorophenyl)ethenesulfonamide,

N-(n-[n-decyl]-N-[p-ethylphenyl]carbamoyl)-2-(m-methoxyphenyl)propene-1-sulfonamide,

N-(n-methyl-N-[p-tert-butylphenyl]carbamoyl)-2-(p-tolyl)ethenesulfonamide,

N-(n-[n-propyl]-N-[m-isopropoxyphenyl]carbamoyl)-2-(p-fluorophenyl)ethenesulfonamide,

N-(n-[isopropyl]-N-[p-n-butoxyphenyl]carbamoyl)-2-phenylbut-1-ene-1-sulfonamide,

N-(n-allyl-N-phenylcarbamoyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(n-benzyl-N-phenylcarbamoyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(piperidinocarbonyl)-2-(p-isopropoxyphenyl)ethenesulfonamide,

N-([4-benzylpiperidino]carbonyl)-2-(m-chlorophenyl)ethenesulfonamide,

N-([4-(3-phenylprop-1-yl)piperidino]carbonyl)-2-phenylethenesulfonamide,

N-([4-(3-phenylprop-1-yl)piperidino]carbonyl)-2-(p-chlorophenylethenesulfonamide,

N-(morpholinocarbonyl)-1,2-diphenylethenesulfonamide and

N-([1,2,3,4-tetrahydroisoquinolino]carbonyl)-2-phenylethenesulfonamide,

respectively.

EXAMPLE IX N-(N-[Bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-phenylethenesulfonamide

To a solution of 1.8 g. of 2-phenylethenesulfonamide and 4.8 g. of1,1-diphenyl-3-(bicyclo[2.2.1]hept-2-en-5-ylmethyl)urea in 20 ml. ofN,N-dimethylformamide, is added, with stirring, 0.64 g. of a 56.6%dispersion of sodium hydride in mineral oil. The mixture is stirred atambient temperature overnight, during which time a heavy precipitateforms. To the reaction mixture is then added 200 ml. of ether. Afterstirring for 15 minutes, the precipitate is filtered off. It isdissolved in 50 ml. of water, and then the crude product is precipitatedby acidification using concentrated hydrochloric acid. It is filteredoff and recrystallized from aqueous acetone. The yield is 1.9 g. (56%)of a solid, m.p. 161°-163.5° C.

Analysis -- Calc'd for C₁₇ H₂₀ N₂ O₃ S (percent): C, 61.43; H, 6.07; N,9.43. Found (percent): C, 61.13; H, 5.95; N, 8.30.

When the above procedure is repeated, and the 2-phenylethenesulfonamideis replaced by an equimolar amount of 2-phenylpropene-1-sulfonamide,1-phenylpropene-2-sulfonamide, 3-phenylbut-2-ene-2-sulfonamide,1-phenylbut-1-ene-2-sulfonamide, 2,2-diphenylethenesulfonamide,2-(p-chlorophenyl)ethenesulfonamide, 2-(m-tolyl)ethenesulfonamide,2-(p-methoxyphenyl)ethenesulfonamide and2-(p-chlorophenyl)propene-1-sulfonamide, respectively, there isproduced:

N-(n-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-1-phenylpropene-1-sulfonamide,

N-(n-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-3-phenylbut-2-ene-2-sulfonamide,

N-(n-[bicylco[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(n-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2,2-diphenylethenesulfonamide,

N-(n-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(n-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-(m-tolyl)ethenesulfonamide,

N-(n-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-(p-methoxyphenyl)ethenesulfonamideand

N-(n-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-(p-chlorophenyl)propene-1-sulfonamide,

respectively.

EXAMPLE X

Following the procedure of Example IX, and using2-phenylethenesulfonamide and1,1-diphenyl-3-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)urea asstarting materials, is preparedN-(N-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-2-phenylethenesulfonamide,m.p. 176°-178° C.

Analysis -- Calc'd for C₁₆ H₂₀ N₂ O₄ S (percent): C, 57.13; H, 5.99; N,8.33. Found (percent): C, 56.83; H, 6.06; N, 8.24.

Again following the procedure of Example IX, and using2-phenylethenesulfonamide and1,1-diphenyl-3-(exo-7-oxabicyclo[2.2.1]haptan-2-ylmethyl)urea asstarting materials, is preparedN-(N-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-2-phenylethenesulfonamide,m.p. 150°-152° C.

Analysis -- Calc'd for C₁₆ H₂₀ N₂ O₄ S (percent): C, 57.13; H, 5.99; N,8.33. Found (percent): C, 56.88; H, 6.04; N, 8.28.

Condensation of1,1-diphenyl-3-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)urea with2-phenylpropene-1-sulfonamide, 3-phenylbut-2-ene-2-sulfonamide,2,2-diphenylethenesulfonamide, 2-(m-chlorophenyl)ethenesulfonamide,2-(m-methoxyphenyl)ethenesulfonamide and2-(p-chlorophenyl)propene-1-sulfonamide, respectively, according to theprocedure of Example VIII, produces:

N-(n-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-3-phenylbut-2-ene-2-sulfonamide,

N-(n-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-2,2-diphenylethenesulfonamide,

N-(n-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-2-(m-chlorophenyl)ethenesulfonamide,

N-(n-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-2-(m-methoxyphenyl)ethenesulfonamideand

N-(n-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl-2-(p-chlorophenyl)propene-1-sulfonamide,

respectively.

In like manner, condensation of1,1-diphenyl-3-(exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)urea with1-phenylpropene-2-sulfonamide, 1-phenylbut-1-ene-2-sulfonamide,2-(p-chlorophenyl)ethenesulfonamide,2-(p-isopropylphenyl)ethenesulfonamide and1-(p-chlorophenyl)propene-2-sulfonamide, respectively, according to theprocedure of Example VIII, affords:

N-(n-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(n-[exo-7-oxabicyclo[2.2.1]heptan-]-ylmethyl]carbamoyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(n-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-2-(p-isopropylphenyl)ethenesulfonamide,and

N-(n-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

respectively.

EXAMPLE XI N-(Piperidinocarbonyl)-1-phenylpropene-2-sulfonamide

A solution of 1.9g. ofN-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide and 1.7g ofpiperidine in 10ml. of N,N-dimethylformamide is maintained at ca. 95°C.for 6 hours. It is then cooled to ambient temperature, and 100 ml. ofether is added. The mixture is extracted with 50 ml. of water, and thenthe water extract is acidified using concentrated hydrochloric acid.This causes the crude product to precipitate. It is filtered off, andthen it is recrystallized from a mixture of acetone and water giving 670mg. of N-(piperidinocarbonyl)-1-phenylpropene-2-sulfonamide, m.p.159°-161° C.

Analysis--Calcd. for C₁₅ H₂₀ N₂ O₃ S (percent): C, 58.43; H, 6.54; N,9.09. Found (percent): C, 58.21; H, 6.50; N, 9.05.

EXAMPLE XII

Following the procedure of Example XI, and reacting eitherN-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide orN-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide with the appropriateamine, the following compounds are prepared: ##SPC9##

    __________________________________________________________________________                                       Analysis                                                                      Calc'd (%)   Found (%)                      A    B     Z              m.p. (°C.)                                                                     C    H   N   C    H   N                    __________________________________________________________________________    hydrogen                                                                           hydrogen                                                                           N-(bicyclo[2.2.1]heptan-2-yl-                                                                  175-177 61.07                                                                              6.58                                                                              8.38                                                                              61.24                                                                              6.77                                                                              8.10                           methyl)amino                                                        hydrogen                                                                           hydrogen                                                                           N-methyl-N-(2-phenylethyl)-                                                                    143-144.5                                                                             62.78                                                                              5.85                                                                              8.14                                                                              62.77                                                                              5.89                                                                              8.06                           amino                                                               hydrogen                                                                           hydrogen                                                                           4-benzylpiperidino                                                                             175-177 65.61                                                                              6.29                                                                              7.29                                                                              65.66                                                                              6.45                                                                              7.16                 hydrogen                                                                           hydrogen                                                                           1,2,5,6-tetrahydropyridino                                                                     170-172 57.53                                                                              5.52                                                                              9.59                                                                              57.55                                                                              5.58                                                                              9.56                 hydrogen                                                                           hydrogen                                                                           4-propylpiperidino                                                                             146-148 60.70                                                                              7.19                                                                              8.33                                                                              60.48                                                                              8.67                                                                              8.17                 hydrogen                                                                           hydrogen                                                                           2-ethylpiperidino                                                                              138-140 59.61                                                                              6.88                                                                              8.69                                                                              59.51                                                                              6.85                                                                              8.65                 hydrogen                                                                           hydrogen                                                                           N-(azacycloheptan-1-yl)amino                                                                   128-129 58.43                                                                              6.54                                                                              9.09                                                                              58.20                                                                              6.51                                                                              9.04                 hydrogen                                                                           hydrogen                                                                           2-(2-hydroxyethyl)piperidino                                                                   180-181.5                                                                             56.79                                                                              6.55                                                                              8.28                                                                              56.38                                                                              6.49                                                                              8.25                 hydrogen                                                                           hydrogen                                                                           2-methylpiperidino                                                                             138-140 58.43                                                                              6.54                                                                              9.09                                                                              58.00                                                                              6.46                                                                              9.32                 hydrogen                                                                           hydrogen                                                                           N,N-di(2-methylprop-1-yl)-                                                                     157.5-158.5                                                                           60.34                                                                              7.74                                                                              8.28                                                                              60.17                                                                              7.68                                                                              8.29                           amino                                                               hydrogen                                                                           hydrogen                                                                           N,N-diisopropylamino                                                                           168-169 58.00                                                                              7.15                                                                              9.03                                                                              57.60                                                                              7.08                                                                              8.91                 hydrogen                                                                           hydrogen                                                                           N-(azacyclooctan-1-yl)amino                                                                    107-109 59.61                                                                              6.88                                                                              8.69                                                                              59.45                                                                              6.79                                                                              8.68                 hydrogen                                                                           hydrogen                                                                           thiomorpholino   163-166 50.00                                                                              5.16                                                                              8.97                                                                              49.95                                                                              5.25                                                                              8.99                 hydrogen                                                                           hydrogen                                                                           3,5-dimethylpiperidino                                                                         149-151 59.61                                                                              6.88                                                                              8.69                                                                              59.64                                                                              6.88                                                                              8.56                 hydrogen                                                                           hydrogen                                                                           N-benzyl-N-ethylamino                                                                          79-80   62.78                                                                              5.85                                                                              8.14                                                                              62.66                                                                              5.82                                                                              8.13                 hydrogen                                                                           hydrogen                                                                           4-methylpiperidino                                                                             169-171 58.43                                                                              6.54                                                                              9.09                                                                              58.09                                                                              6.40                                                                              9.07                 hydrogen                                                                           methyl                                                                             piperidino       159-161 58.43                                                                              6.54                                                                              9.09                                                                              58.21                                                                              6.50                                                                              9.05                 hydrogen                                                                           hydrogen                                                                           N,N-di(ethoxycarbonylmethyl)-                                                                  112-114 51.25                                                                              5.57                                                                              7.03                                                                              51.10                                                                              5.60                                                                              7.02                           amino                                                               hydrogen                                                                           methyl                                                                             1,2,3,4-tetrahydroisoquinolino                                                                 147-148.5                                                                             64.03                                                                              5.66                                                                              7.86                                                                              64.01                                                                              5.67                                                                              7.89                 hydrogen                                                                           methyl                                                                             pyrrolidino      151-153 57.13                                                                              6.17                                                                              9.52                                                                              56.92                                                                              6.09                                                                              9.47                 hydrogen                                                                           methyl                                                                             morpholino       145-147 54.19                                                                              5.85                                                                              9.03                                                                              54.14                                                                              5.89                                                                              8.98                 hydrogen                                                                           methyl                                                                             N,N-diethylamino 122-124 56.73                                                                              6.74                                                                              9.45                                                                              56.39                                                                              6.80                                                                              9.38                 hydrogen                                                                           hydrogen                                                                           4-phenylpiperidino                                                                             135-137 64.78                                                                              5.98                                                                              7.56                                                                              64.90                                                                              6.28                                                                              7.41                 hydrogen                                                                           hydrogen                                                                           4-(3-phenylpropyl)piperidino                                                                   131.5-133                                                                             66.97                                                                              6.84                                                                              6.79                                                                              66.68                                                                              7.11                                                                              6.92                 hydrogen                                                                           hydrogen                                                                           4-methoxypiperidino                                                                            154.5-156.5                                                                           55.55                                                                              6.22                                                                              8.64                                                                              55.59                                                                              6.22                                                                              8.54                 hydrogen                                                                           hydrogen                                                                           N,N-didecylamino*                                                                              154-157 65.87                                                                              9.34                                                                              5.30                                                                              66.11                                                                              9.12                                                                              5.29                 hydrogen                                                                           hydrogen                                                                           N-(ethoxycarbonylmethyl)-N-                                                                    130-133 59.69                                                                              5.51                                                                              6.96                                                                              59.54                                                                              5.53                                                                              6.89                           benzylamino                                                         hydrogen                                                                           hydrogen                                                                           N-(ethoxycarbonylmethyl)-N-                                                                    126-128 51.51                                                                              5.56                                                                              8.58                                                                              51.62                                                                              5.50                                                                              8.46                           methylamino                                                         hydrogen                                                                           methyl                                                                             4-(3-phenylpropyl)piperidino                                                                   129-131 67.57                                                                              7.08                                                                              6.56                                                                              67.70                                                                              7.22                                                                              6.32                 hydrogen                                                                           hydrogen                                                                           3,4-dichloropiperidino                                                                         195-197 46.27                                                                              4.44                                                                              7.71                                                                              46.32                                                                              4.39                                                                              7.61                 hydrogen                                                                           hydrogen                                                                           4-(3-[4-methoxyphenyl]propyl)-                                                                 214-216 62.09                                                                              6.25                                                                              6.03                                                                              62.13                                                                              6.46                                                                              5.99                           piperidino*                                                         hydrogen                                                                           hydrogen                                                                           morpholino       174-176                                            hydrogen                                                                           hydrogen                                                                           1,2,3,4-tetrahydroisoquinolino                                                                 165-167                                            hydrogen                                                                           hydrogen                                                                           pyrrolidino      199                                                hydrogen                                                                           hydrogen                                                                           N,N-diethylamino 113-115                                            __________________________________________________________________________     *This compound is isolated, and analyzed, as its sodium salt.            

EXAMPLE XIII

Reaction of the appropriate N-(N,N-diphenylcarbamoyl)alkenesulfonamide,selected from those described in Examples IV, V and VII, with theappropriate amine, according to the procedure of Example XI, affords thefollowing congeners:

N-(piperidinocarbonyl)-2-(4-biphenylyl)ethenesulfonamide,

N-(piperidinocarbonyl)-2-phenylpropene-1-sulfonamide,

N-(piperidinocarbonyl)-2,2-diphenylethenesulfonamide,

N-(piperidinocarbonyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(piperidinocarbonyl)-2-(m-chlorophenyl)ethenesulfonamide,

N-(piperidinocarbonyl)-2-(p-methoxyphenyl)propene-1-sulfonamide,

N-([4-hydroxypiperidino]carbonyl)-2-(p-fluorophenyl)-propene-1-sulfonamide,

N-([4hydroxypiperidino]carbonyl)-2-(p-tert-butylphenyl)ethenesulfonamide,

N-([4-methoxypiperidino]carbonyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

N-([4-methoxypiperidino]carbonyl)-2-(p-ethylphenyl)ethenesulfonamide,

N-([4-phenylpiperidino]carbonyl)-2-phenylpropene-1-sulfonamide,

N-([4-phenylpiperidino]carbonyl)-1-phenylpropene-2-sulfonamide,

N-([4-phenylpiperidino]carbonyl)-2,2-diphenylethenesulfonamide,

N-([4-phenylpiperidino]carbonyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-([4-phenylpiperidino]carbonyl)-2-(p-tolyl)but-1-ene-1-sulfonamide,

N-([4-propylpiperidino]carbonyl)-1-phenylpropene-2-sulfonamide,

N-([4-methylpiperidino]carbonyl)-2-(m-bromophenyl)propene-1-sulfonamide,

N-([2-methylpiperidino]carbonyl)-2,2-diphenylethenesulfonamide,

N-([3-methylpiperidino]carbonyl)-2-(p-butoxyphenyl)ethenesulfonamide,

N-([2-ethylpiperidino]carbonyl]-1-(p-chlorophenyl)propene-2-sulfonamide,

N-([2-ethylpiperidino]carbonyl)-2-(m-methoxyphenyl)but-1-ene-1-sulfonamide,

N-([4-benzylpiperidino]carbonyl)-2-phenylpropene-1-sulfonamide,

N-([4-benzylpiperidino]carbonyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

N-([4-benzylpiperidino]carbonyl)-2-(m-bromophenyl)ethenesulfonamide,

N-([4-benzylpiperidino]carbonyl)-2-(p-fluorophenyl)ethenesulfonamide,

N-([4-benzylpiperidino]carbonyl)-1-(p-ethoxyphenyl)propene-2-sulfonamide,

N-([4-benzylpiperidino]carbonyl)-2-(p-tolyl)but-1-ene-1-sulfonamide,

N-([4-(2-phenylethyl)piperidino]carbonyl)-2-phenylethenesulfonamide,

N-([4-(2-phenylethyl)piperidino]carbonyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-([4-(2-phenylethyl)piperidino]carbonyl)-2-(p-isopropylphenyl)propene-1-sulfonamide,

N-([4-(2-phenylethyl)piperidino]carbonyl)-2-(m-isopropoxyphenyl)ethenesulfonamide,

N-([4-(2-phenylethyl)piperidino]carbonyl)-2-(p-fluorophenyl)ethenesulfonamide,

N-(azacycloheptan-1-ylcarbonyl)-1-phenylpropene-2-sulfonamide,

N-(azacycloheptan-1-ylcarbonyl)-2-(o-chlorophenyl)ethenesulfonamide,

N-(azacycloheptan-1-ylcarbonyl)-3-phenylbut-2-ene-2-sulfonamide,

N-(pyrrolidinocarbonyl)-2-(m-chlorophenyl)ethenesulfonamide,

N-(pyrrolidinocarbonyl)-2-(m-tolyl)ethenesulfonamide,

N-(morpholinocarbonyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(morpholinocarbonyl)-2-(p-chlorophenyl)propene-1-sulfonamide,

N-(morpholinocarbonyl)-2-(m-isopropoxyphenyl)-ethenesulfonamide,

N-(morpholinocarbonyl)-(p-isopropylphenyl)propene-1-sulfonamide,

N-(morpholinocarbonyl)-2,2-diphenylethenesulfonamide,

N-(morpholinocarbonyl)-1,2-diphenylpropene-1-sulfonamide,

N-(thiomorpholinocarbonyl)-2-(p-bromophenyl)ethenesulfonamide,

N-(thiomorpholinocarbonyl)-2-(p-fluorophenyl)propene-1-sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenylpropene-1-sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenylbut-1-ene-1-sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(m-chlorophenyl)ethenesulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(p-bromophenyl)ethenesulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(p-tert-butylphenyl)ethenesulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(p-fluorophenyl)propene-1-sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(m-methoxyphenyl)but-1-ene-1-sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(n,n-dimethylcarbamoyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(n,n-diethylcarbamoyl)-2-(m-tolyl)propene-1-sulfonamide,

N-(n,n-diisopropylcarbamoyl)-2-(m-isopropoxyphenyl)ethenesulfonamide,

N-(n,n-diallylcarbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n,n-diallylcarbamoyl)-2-(p-chlorophenyl)propene-1-sulfonamide,

N-(n-[2-methylallyl]carbamoyl)-1-(p-tolyl)propene-2-sulfonamide,

N-(n-[4-methylpent-3-enyl]carbamoyl)-1-(m-methoxyphenyl)but-1-ene-2-sulfonamide,

N-(n-methyl-N-allylcarbamoyl)-2-(p-fluorophenyl)-ethenesulfonamide,

N-(n-methyl-N-cyclohexyl)-2-phenylethenesulfonamide,

N-(n,n-dicyclohexylcarbamoyl)-3-(p-chlorophenyl)but-2-ene-2-sulfonamide,

N-(n-[2-phenylethyl]carbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n-methyl-N-[2-phenylethyl]carbamoyl)-2-(p-chlorophenyl)ethenesulfonamide

N-(4-[4-phenylbutyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(4-[5-phenylpentyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(3-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(2-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(4-[2-(p-isopropoxyphenyl)ethyl]piperidinocarbonyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(3-[3-(p-butoxyphenyl)propyl]piperidinocarbonyl)-2-(o-tolyl)ethenesulfonamide,

N-(3-[3-(p-isopropylphenyl)propyl]piperidinocarbonyl)-2-phenylpropene-1-sulfonamide,

N-(4-[3-(p-t-butylphenyl)propyl]piperidinocarbonyl)-1-phenylpropene-2-sulfonamide,

N-(4-[m-methylbenzyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(4-[3-(m-methoxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(4-[3-(o-methoxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(4-[2-(p-methoxyphenyl)ethyl]piperidinocarbonyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(4-[4-(m-methoxyphenyl)butyl]piperidinocarbonyl)-1-(p-tolyl)propene-2-sulfonamide,

N-(4-[2-phenylprop-1-yl]piperidinocarbonyl)-2-phenylethenesulfonamide,and

N-(4-[2-phenylbut-1-yl]piperidinocarbonyl)-2-(p-chlorophenyl)ethenesulfonamide,

respectively.

EXAMPLE XIV

The procedure of Example XI is repeated, except that the piperidine usedtherein is replaced by an equimolar amount of4-(3-phenylpropyl)piperidine, and theN-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide used therein isreplaced by:

N-(n-phenyl-N-[p-chlorophenyl]carbamoyl)-2-phenylethenesulfonamide,

N-(n-phenyl-N-[p-chlorophenyl]carbamoyl)-2-(p-methoxyphenyl)ethenesulfonamide,

N-(n,n-di[p-methoxyphenyl]carbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

N-(n-[n-butyl]-N-[p-tolyl]carbamoyl)-2-(o-chlorophenyl)ethenesulfonamide,

N-(n-methyl-N-[p-tert-butylphenyl]carbamoyl)-2-(p-tolyl)ethenesulfonamide,

N-(n-[n-propyl]-N-[m-isopropoxyphenyl]carbamoyl)-2-(p-fluorophenyl)ethenesulfonamideand

N-(n-benzyl-N-phenylcarbamoyl)-1-phenylbut-1-ene-2-sulfonamide,

respectively.

This affords:

N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-phenylethenesulfonamide,

N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-(p-methoxyphenyl)ethenesulfonamide,

N-([4-(3-phenylpropyl)piperidino]carbonyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-(o-chlorophenyl)ethenesulfonamide,

N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-(p-tolyl)ethenesulfonamide,

N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-(p-fluorophenyl)ethenesulfonamideand

N-([4-(3-phenylpropyl)piperidino]carbonyl)-1-phenylbut-1-ene-2-sulfonamide,

respectively.

EXAMPLE XVN-(N-[1-Methoxycarbonylethyl]carbamoyl)-2-phenylethenesulfonamide

To a solution of 3.5 g. of DL-alanine methyl ester hydrochloride in 20ml. of N,N-dimethylformamide is added 1.05 g. of a 56.6% suspension ofsodium hydride in mineral oil. The mixture is stirred at ambienttemperature for 15 minutes, and then 3.8 g. ofN-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide is added. The wholereaction mixture is then maintained at ca. 90° C. for 40 minutes. Afterbeing allowed to cool to room temperature, it is diluted with an excessof ether and then it is extracted with water. Acidification of the waterextract with dilute hydrochloric acid causes precipitation of the crudeproduct, which is then filtered off. The ether phase is washed withdilute hydrochloric acid, which causes a further crop of product toprecipitate. It is filtered off and the two crops of product arecombined. This yields 1.55 g. of material having a melting point of135°-139° C. The crude product is recrystallized from a mixture ofacetone and hexane, giving 0.70 g. ofN-[N-(1-methoxycarbonylethyl)carbamoyl]-2-phenylethenesulfonamide, m.p.138°-140° C.

Analysis -- Calc'd for C₁₃ H₁₆ N₂ O₅ S (percent): C, 49.94; H, 5.12; N,8.96. Found (percent): C, 50.06; H, 5.26; N, 9.32.

EXAMPLE XVI

Following the procedure of Example XIV, and replacing the DL-alaninemethyl ester hydrochloride used therein by the appropriate amino-esterhydrochloride, the following compounds are prepared. ##SPC10##

    __________________________________________________________________________                      Analysis                                                                M.P.  Calc'd (%)   Found (%)                                       Z          (°C.)                                                                        C    H   N   C    H   N                                     __________________________________________________________________________    N-(1-ethoxycarbonyl-                                                                      127-129                                                                             54.23                                                                              6.26                                                                              7.91                                                                              54.23                                                                              6.29                                                                              7.93                                  2-methylprop-1-yl)-                                                           amino                                                                         N-(1-ethoxycarbonyl-                                                                      126-128                                                                             55.43                                                                              6.56                                                                              7.61                                                                              55.52                                                                              6.54                                                                              7.48                                  2-methylbut-1-yl-                                                             amino                                                                         N-(1-ethoxycarbonyl-                                                                      81-83 55.43                                                                              6.56                                                                              7.61                                                                              55.25                                                                              6.49                                                                              7.77                                  pent-1-yl)amino                                                               N-(5-ethoxycarbonyl-                                                                      97-99 55.43                                                                              6.56                                                                              7.61                                                                              55.50                                                                              6.56                                                                              7.65                                  pent-1-yl)amino                                                               N-(1,3-dimethoxycar-                                                                      120-122                                                                             50.00                                                                              5.25                                                                              7.29                                                                              49.89                                                                              5.22                                                                              7.11                                  bonylprop-1-yl)amino                                                          N-(1-ethoxycarbonyl-                                                                      149-151                                                                             52.92                                                                              5.92                                                                              8.23                                                                              52.69                                                                              5.89                                                                              8.23                                  prop-1-yl)amino                                                               N-(3-ethoxycarbonyl-                                                                      120-122                                                                             52.92                                                                              5.92                                                                              8.23                                                                              52.76                                                                              5.90                                                                              8.28                                  prop-1-yl)amino                                                               __________________________________________________________________________

EXAMPLE XVII

When the procedure of Example XV is repeated, and the alkenesulfonamidecomponent is:

1-phenylpropene-2-sulfonamide,

2-phenylpropene-1-sulfonamide,

2-(p-chlorophenyl)ethenesulfonamide,

1,1-diphenylethenesulfonamide,

2-(p-tolyl)ethenesulfonamide,

1-phenylpropene-2-sulfonamide,

2-phenylpropene-1-sulfonamide,

2-(m-chlorophenyl)ethenesulfonamide,

2-(p-bromophenyl)ethenesulfonamide,

1-(m-methoxyphenyl)propene-2-sulfonamide,

2-(p-fluorophenyl)ethenesulfonamide,

3-phenylbut-2-ene-2-sulfonamide,

2-phenylbut-1-ene-1-sulfonamide,

2-(p-chlorophenyl)propene-1-sulfonamide,

2-(p-isopropylphenyl)propene-1-sulfonamide,

2-phenylpropene-1-sulfonamide,

2-(o-chlorophenyl)ethenesulfonamide,

1-phenylbut-1-ene-2-sulfonamide,

1,2 -diphenylethenesulfonamide,

2-phenylethenesulfonamide,

1-(m-chlorophenyl)propene-2-sulfonamide,

2-(m-tolyl)ethenesulfonamide and

2-(p-isopropoxyphenyl)ethenesulfonamide,

respectively, and the amino-acid ester hydrochloride component is thehydrochloride salt of:

glycine methyl ester,

glycine methyl ester,

glycine methyl ester,

glycine methyl ester,

glycine methyl ester,

glycine ethyl ester,

glycine ethyl ester,

glycine ethyl ester,

glycine ethyl ester,

glycine ethyl ester,

Dl-alanine methyl ester,

Dl-alanine methyl ester,

Dl-alanine methyl ester,

Dl-alanine methyl ester,

Dl-alanine methyl ester,

Dl-leucine ethyl ester,

Dl-leucine ethyl ester,

Dl-leucine ethyl ester,

Dl-leucine ethyl ester,

ω-aminooctanoic acid ethyl ester,

ω-aminooctanoic acid ethyl ester,

ω-aminooctanoic acid ethyl ester and

ω-aminooctanoic acid ethyl ester,

respectively, there is produced:

N-(n-[methoxycarbonylmethyl]carbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n-[methoxycarbonylmethyl]carbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[methoxycarbonylmethyl]carbamoyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(n-[methoxycarbonylmethyl]carbamoyl)-1,1-diphenylethenesulfonamide,

N-(n-[methoxycarbonylmethyl]carbamoyl)-2-(p-tolyl)-ethenesulfonamide,

N-(n-[ethoxycarbonylmethyl]carbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n-[ethoxycarbonylmethyl]carbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[ethoxycarbonylmethyl]carbamoyl)-2-(m-chlorophenyl)ethenesulfonamide,

N-(n-[ethoxycarbonylmethyl]carbamoyl)-2-(p-bromophenyl)ethenesulfonamide,

N-(n-[ethoxycarbonylmethyl]carbamoyl)-1-(m-methoxyphenyl)propene-2-sulfonamide,

N-(n-[1-methoxycarbonylethyl]carbamoyl)-2-(p-fluorophenyl)ethenesulfonamide

N-(n-[1-methoxycarbonylethyl]carbamoyl)-3-phenylbut-2-ene-2-sulfonamide,

N-(n-[1-methoxycarbonylethyl]carbamoyl)-2-phenylbut-1-ene-1-sulfonamide,

N-(n-[1-methoxycarbonylethyl]carbamoyl)-2-(p-chlorophenyl)propene-1-sulfonamide,

N-(n-[1-methoxycarbonylethyl]carbamoyl)-2-(p-isopropylphenyl)propene-1-sulfonamide,

N-(n-[1-ethoxycarbonyl-2-methylbut-1-yl]carbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[1-ethoxycarbonyl-2-methylbut-1-yl]carbamoyl)-2-(o-chlorophenyl)ethenesulfonamide,

N-(n-[1-ethoxycarbonyl-2-methylbut-1-yl]carbamoyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(n-[1-ethoxycarbonyl-2-methylbut-1-yl]carbamoyl)-1,2-diphenylethenesulfonamide,

N-(n-[7-ethoxycarbonylhept-1-yl]carbamoyl)-2-phenylethenesulfonamide,

N-(n-[7-ethoxycarbonylhept-1-yl]carbamoyl)-1-(m-chlorophenyl)propene-2-sulfonamide,

N-(n-[7-ethoxycarbonylhept-1-yl]carbamoyl)-2-(m-tolyl)ethenesulfonamideand

N-(n-[7-ethoxycarbonylhept-1-yl]carbamoyl)-2-(p-isopropoxyphenyl)ethenesulfonamide,

respectively.

The amino-acid ester hydrochlorides used in this Example are eitheritems of commerce, or they are prepared from the correspondingamino-acids (which are all items of commerce) by esterification.Procedures for the esterification of amino-acids are discussed byGreenstein and Winitz in the "Chemistry of the Amino-acids," John Wileyand Sons, Inc., New York-London, 1961, Volume 2, pp. 925-927.

EXAMPLE XVIII

When the procedure of Example XIV is repeated, and the DL-alanine methylester hydrochloride used therein is replaced by an equimolar amount ofN-phenylglycine ethyl ester hydrochloride and N-p-chlorophenylglycineethyl ester hydrochloride, respectively, this affords:

N-(n-phenyl-N-[ethoxycarbonylmethyl]carbamoyl)-2-phenylethenesulfonamideand

N-(n-[p-chlorophenyl]-N-[ethoxycarbonylmethyl]carbamoyl)-2-phenylethenesulfonamide,respectively.

EXAMPLE XIX N-(Pyrrolidinocarbonyl)-2-phenylethenesulfonamide

A mixture of 3.4 g. ofN-(N-[m-chlorophenyl]carbamoyl)-2-phenylethenesulfonamide and 2.15 g. ofpyrrolidine in 100 ml. of ethanol is heated under reflux for 20 hours.The solution is cooled, and then it is concentrated in vacuo to ca. 25ml. A small amount of starting material precipitates and it is filteredoff. To the ethanol filtrate is then added 75 ml. of ether and 75 ml. ofwater. The layers are separated, and the aqueous layer is acidifiedusing concentrated hydrochloric acid. This causes the crude product toprecipitate. It is filtered off, and when dry it weighs 1.5 g. The etherlayer is washed with 50 ml. of 1N hydrochloric acid, followed by 25 ml.of water. After being dried using anhydrous sodium sulfate, the ether isevaporated in vacuo to give a second crop of product (0.70 g.). Thefirst crop of product is recrystallized from acetone to 0.60 g. of pureN-(pyrrolidinocarbonyl)-2-phenylethenesulfonamide, m.p. 201°-204° C.

Analysis -- Calc'd for C₁₃ H₁₆ N₂ O₃ S (percent): C, 55.71; H, 5.75; N,10.00. Found (percent): C, 55.45; H, 5.68; N, 9.94.

EXAMPLE XX

Following the procedure of Example XIX and replacing the pyrrolidine bythe appropriate amine, the following compounds are prepared: ##SPC11##

    __________________________________________________________________________                       Analysis                                                                      Calc'd (%)   Found (%)                                      Z          M.P. (°C.)                                                                    C    H   N   C    H   N                                    __________________________________________________________________________    N,N-dibutylamino                                                                          104-105.5                                                                            60.34                                                                              7.74                                                                              8.28                                                                              60.60                                                                              7.50                                                                              8.32                                 morpholino  176-179                                                                              52.70                                                                              5.44                                                                              9.46                                                                              52.63                                                                              5.37                                                                              9.48                                 1,2,3,4-tetrahydro-                                                                       165-167                                                                              63.15                                                                              5.30                                                                              8.18                                                                              63.00                                                                              5.35                                                                              8.26                                 isoquinolino                                                                  3-azabicyclo[3.2.2]-                                                                      181-184                                                                              61.06                                                                              6.63                                                                              8.38                                                                              61.08                                                                              6.66                                                                              8.32                                 nonan-3-yl                                                                    N,N-diethylamino                                                                          110-113                                                                              55.31                                                                              6.43                                                                              9.92                                                                              55.28                                                                              6.29                                                                              9.80                                 4-hydroxypiperidino                                                                       160-165                                                                              54.19                                                                              5.85                                                                              9.03                                                                              54.43                                                                              5.94                                                                              9.24                                 N,N-diheptylamino  65.37                                                                              9.06                                                                              6.63                                                                              65.88                                                                              8.84                                                                              6.71                                 __________________________________________________________________________

When N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide reacts withN,N-dipropylamine according to the procedure of Example XIX, the productis N-(N,N-dipropylcarbamoyl)-2-phenylethenesulfonamide, m.p. 128°-130°C.

Analysis -- Calc'd for C₁₅ H₂₂ N₂ O₃ S (percent): C, 58.05; H, 7.15; N,9.03. Found (percent): C, 57.77; H, 7.09; N, 8.96.

Starting with N-(N-[m-tolyl]carbamoyl)-2-phenylethenesulfonamide andN,N-dibutylamine, and using the procedure of Example XIX, the product isN-(N,N-dibutylcarbamoyl)-2-phenylethenesulfonamide, m.p. 104°-105° C.

Analysis -- Calc'd for C₁₇ H₂₆ N₂ O₃ S (percent): C, 60.34; H, 7.74; N,8.28. Found (percent): C, 60.23; H, 7.58; N, 8.50.

EXAMPLE XXI N-(Piperidinocarbonyl)-2-phenylethenesulfonamide

A slurry of 6.5 g. of 2-phenylethenesulfonamide in 45 ml. of oxalylchloride is stirred and refluxed for 16 hours. It is cooled to ambienttemperature, and then the solid material is filtered off and washed withhexane. When dry, the solid weighs 2.2 g. and has a melting point of170°-180° C.

The above solid is added in small portions with stirring at ambienttemperature, to a solution of 5 ml. of piperidine in 15 ml. of methylenechloride. The mixture is stirred for an additional 1.5 hours after theend of the addition, and then it is evaporated to dryness, in vacuo. Theresidue is partitioned between 40 ml. of water and 25 ml. of ether, thelayers are separated, and the other layer is discarded. The aqueouslayer is acidified with acetic acid, and then it is extracted withether. This latter ether extract is washed with water, dried usinganhydrous sodium sulfate and then finally it is evaporated to dryness invacuo. The residue is 0.60 g. of crude product, m.p. 138°-140° C. Thecrude product is recrystallized from a mixture of methylene chloride andether, to give a pure sample ofN-(N-piperidinocarbamoyl)-2-phenylethenesulfonamide, m.p. 175°-177° C.

Analysis -- Calc'd for C₁₄ H₁₈ N₂ O₃ S (percent): C, 57.13; H, 6.17; N,9.52. Found (percent): C, 57.23; H, 6.11; N, 9.54.

EXAMPLE XXII N-([4-Carboxypiperidino]carbonyl)-2-phenylethenesulfonamide

A mixture of 5 g. of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamideand 10.3 g. of ethyl isonipecotate in 20 ml. of N,N-dimethylformamide ismaintained at ca. 90° C. for 40 minutes. The mixture is cooled toambient temperature, diluted with ether, and then it is extracted withwater. The water extract is acidified using concentrated hydrochloricacid, and then it is extracted with methylene chloride. The driedmethylene chloride is evaporated to dryness in vacuo leaving a viscousoil. The oil is redissolved in a small volume of tetrahydrofuran,absorbed onto a column of silica gel, and then eluted from the columnwith an excess of the same solvent. The solvent is evaporated in vacuo,and the residue is dissolved in 50 ml. of 0.5N sodium hydroxidesolution. After 1 hour it is re-precipitated by acidification, andrecovered by vacuum filtration in the form of white crystals. It is thendissolved in a mixture of 100 ml. of acetone and 100 ml. oftetrahydrofuran, and the solution is concentrated slowly to effectprecipitation of the product. The solid is filtered off, and thentriturated with acetone to give pureN-([4-carboxypiperidino]carbonyl)-2-phenylethenesulfonamide, m.p.179°-181° C.

Analysis -- Calc'd for C₁₅ H₁₈ N₂ O₅ S (percent): C, 53.25; H, 5.32 N,8.28. Found (percent): C, 52.93; H, 5.58; N, 8.04.

EXAMPLE XXIIIN-(4-[3-Phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide

A solution of 12 g. of 4-(3-phenylpropyl)piperidine and 12.5 g. of thepotassium salt of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide(prepared as described in Example IV) in 30 ml. of N,N-dimethylformamideis heated to 75° C., and then 5.7 ml. of glacial acetic acid is addeddropwise, with stirring. The temperature rises to 90° C. during theaddition. The reaction mixture is maintained at 85°-87° C. for a further45 minutes, and then it is allowed to cool to ambient temperature. It ispoured onto a mixture of 200 ml. of 1N sodium hydroxide solution and 100g. of crushed ice. A gummy precipitate forms. A 50-ml. portion of etheris added, and the mixture is stirred vigorously until a turbid solutionis obtained. A 50-ml. portion of hexane is then added, which causes thesodium salt of the product to precipitate. It is filtered off and washedwith water followed by ether. The crude sodium salt is redissolved in amixture of 100 ml. of acetone and 50 ml. of water, and then 5 ml. ofconcentrated hydrochloric acid followed by 100 ml. of water is added.The precipitate which forms is filtered off, washed with aqueousacetone, and finally recrystallized from acetone-hexane to give 6.8 g.(55%) of pureN-(4-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide, m.p.131°-133° C.

EXAMPLE XXIVN-(N-[1-Carboxyprop-1-yl]carbamoyl)-2-phenylethenesulfonamide

To 30 ml. of 1N sodium hydroxide is added 1.0 g. ofN-(N-[1-ethoxycarbonylprop-1-yl]carbamoyl)-2-phenylethenesulfonamide.The mixture is stirred at ambient temperature for 30 minutes, and thenthe small amount of insoluble material is filtered off and discarded.The filtrate is acidified using concentrated hydrochloric acid, whichcauses the product to precipitate. It is filtered off, washed withwater, and then air dried to give 6.0 g. ofN-(N-[1-carboxyprop-1-yl]carbamoyl)-2-phenylethenesulfonamide, m.p.150°-152° C.

Analysis -- Calc'd for C₁₃ H₁₆ N₂ O₅ S (percent): C, 49.98; H, 5.16; N,8.97. Found (percent): C, 49.72; H, 5.20; N, 8.85.

EXAMPLE XXV

Starting with the appropriate ester selected from those of Examples II,XII, XV and XVI, and using the hydrolysis procedure of Example, XXIV,the following compounds are prepared: ##SPC12##

    __________________________________________________________________________                           Analysis                                                                      Calc'd (%)   Found (%)                                 A B   Z         M.P. (°C.)                                                                    C    H   N   C    H   N                                __________________________________________________________________________    H H  N-(1-carboxy-2-                                                                          167.5-169                                                                            57.75                                                                              4.85                                                                              7.48                                                                              57.64                                                                              4.84                                                                              7.22                                  phenylethyl)amino                                                        H H  N-(carboxymethyl)-                                                                       182-183                                                                              46.48                                                                              4.26                                                                              9.86                                                                              46.69                                                                              4.33                                                                              9.86                                  amino                                                                    H CH.sub.3                                                                         N-(carboxymethyl)-                                                                       183-185                                                                              48.32                                                                              4.73                                                                              9.39                                                                              47.99                                                                              4.79                                                                              9.29                                  amino                                                                    H H  N-(1-carboxyethyl)-                                                                      155-156                                                                              48.32                                                                              4.73                                                                              9.39                                                                              48.31                                                                              4.71                                                                              9.14                                  amino                                                                    H H  N-(1-carboxy-3-                                                               methylbut-1-yl)amino                                                                     162-164                                                                              52.92                                                                              5.87                                                                              8.23                                                                              52.56                                                                              5.75                                                                              8.02                             H H  N-(1,3-dicarboxy-                                                                        170-171                                                                              47.19                                                                              4.53                                                                              7.86                                                                              46.98                                                                              4.51                                                                              7.79                                  prop-1-yl)amino                                                          H H  N-(1-carboxy-2-                                                                          155-157                                                                              51.52                                                                              5.56                                                                              8.58                                                                              51.33                                                                              5.74                                                                              8.47                                  methylprop-1-yl)-                                                             amino                                                                    H H  N-(3-carboxyprop-                                                                        133-135                                                                              49.98                                                                              5.16                                                                              8.97                                                                              49.82                                                                              5.22                                                                              8.82                                  1-yl)amino                                                               H H  N-(1-carboxypent-                                                                        140-142                                                                              52.92                                                                              5.92                                                                              8.23                                                                              58.85                                                                              6.00                                                                              8.22                                  1-yl)amino                                                               H H  N-(5-carboxypent-                                                                        154-155.5                                                                            52.92                                                                              5.92                                                                              8.23                                                                              53.07                                                                              5.98                                                                              8.17                                  1-yl)amino                                                               H H  N-(1-carboxy-2-meth-                                                                     130-133                                                                              50.40                                                                              5.92                                                                              7.83                                                                              50.69                                                                              5.71                                                                              7.87                                  ylbut-1-yl)amino*                                                        H H  N-(1-carboxyhept-1-                                                                      142-144                                                                              55.41                                                                              6.57                                                                              7.60                                                                              55.86                                                                              6.70                                                                              7.37                                  yl)amino                                                                 H H  N-(carboxymethyl)-                                                                       127-128                                                                              57.75                                                                              4.85                                                                              7.48                                                                              57.40                                                                              4.82                                                                              7.20                                  N-benzylamino                                                            __________________________________________________________________________     *This material is isolated, and analyzed as a monohydrate.               

EXAMPLE XXVI

Starting with the appropriate ester, selected from those of ExamplesIII, XII, XVII and XVIII, and using the hydrolysis procedure of ExampleXXIV, the following compounds are prepared:

N-(n-[carboxymethyl]carbamoyl)-2-(m-methoxyphenyl)propene-1-sulfonamide,

N-(n-[carboxymethyl]carbamoyl)-2-(p-biphenylyl)propene-1-sulfonamide,

N-(n,n-di[carboxymethyl]carbamoyl)-2-phenylethenesulfonamide,

N-(n-[carboxymethyl]-N-methyl)carbamoyl)-2-phenylethenesulfonamide,

N-(n-[carboxymethyl]carbamoyl)-1-phenylpropene-2-sulfonamide,

N-(n-[carboxymethyl]carbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[carboxymethyl]carbamoyl)-2-(p-chlorophenyl)-ethenesulfonamide,

N-(n-[carboxymethyl]carbamoyl)-1,1-diphenylethenesulfonamide,

N-(n-[carboxymethyl]carbamoyl)-2-(p-tolyl)ethenesulfonamide,

N-(n-[carboxymethyl]carbamoyl)-2-(m-chlorophenyl)ethenesulfonamide,

N-(n-[carboxymethyl]carbamoyl)-2-(p-bromophenyl)ethenesulfonamide,

N-(n-[carboxymethyl]carbamoyl)-1-(m-methoxyphenyl)propene-2-sulfonamide,

N-(n-[1-carboxyethyl]carbamoyl)-2-(p-fluorophenyl)-ethenesulfonamide,

N-(n-[1-carboxyethyl]carbamoyl)-3-phenylbut-2-ene-2-sulfonamide,

N-(n-[1-carboxyethyl]carbamoyl)-2-phenylbut-1-ene-1-sulfonamide,

N-(n-[1-carboxyethyl]carbamoyl)-2-(p-chlorophenyl)propene-1-sulfonamide,

N-(n-[1-carboxyethyl]carbamoyl)-2-(p-isopropylphenyl)propene-1-sulfonamide,

N-(n-[1-carboxy-2-methylbut-1-yl]carbamoyl)-2-phenylpropene-1-sulfonamide,

N-(n-[1-carboxy-2-methylbut-1-yl]carbamoyl)-2-(o-chlorophenyl)ethenesulfonamide,

N-(n-[1-carboxy-2-methylbut-1-yl]carbamoyl)-1-phenylbut-1-ene-2-sulfonamide

N-(n-[1-carboxy-2-methylbut-1-yl]carbamoyl)-1,2-diphenylethenesulfonamide,

N-(n-[7-carboxyhept-1-yl]carbamoyl)-2-phenylethenesulfonamide,

N-(n-[7-carboxyhept-1-yl]carbamoyl)-1-(m-chlorophenyl)propene-2-sulfonamide

N-(n-[7-carboxyhept-1-yl]carbamoyl-2-(m-tolyl)ethenesulfonamide,

N-(n-[7-carboxyhept-1-yl]carbamoyl)-2-(p-isopropoxyphenyl)ethenesulfonamide

N-(n-phenyl-N-[carboxymethyl]carbamoyl)-2-phenylethenesulfonamide and

N-(n-[p-chlorophenyl]-N-[carboxymethyl]carbamoyl)-2-phenylethenesulfonamide

respectively.

EXAMPLE XXVIIN-(N-[1-carboxyhetp-1-yl]carbamoyl)-2-phenylethenesulfonamide

To 40 ml. of N,N-dimethylformamide is added 10.05 g. of ethyl2-aminooctanoate hydrochloride followed by 2.1 g. of a 56.6% dispersionof sodium hydride in mineral oil. The mixture is stirred at ambienttemperature for 15 minutes, and then 7.6 g. ofN-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide is added. Thereaction mixture is then heated at ca. 100°C. for 1 hr. After beingallowed to cool back to ambient temperature, the mixture is diluted withan excess of ether and then it is extracted with water. When the waterextract is acidified using concentrated hydrochloric acid, an oilseparates. The supernatant aqueous layer is decanted off, and replacedby 50 ml. of ether and 50 ml. of fresh water. The ether layer isremoved, dried using anhydrous sodium sulfate, and then evaporated invacuo. The residue is an oil, which resists attempts to induce it tosolidify. The oil is dissolved in acetone, and 50 ml. of 1N sodiumhydroxide is added. A heterogeneous mixture is formed, which is stirredat ambient temperature overnight. The mixture is then extracted withether, and the extract is discarded. The residual aqueous phase isacidified using concentrated hydrochloric acid, and the oil whichprecipitates is extracted into ether. The etheral solution is dried (Na₂SO₄), treated with decolorizing charcoal, and then evaporated in vacuo.An oil is obtained, which slowly crystallizes on standing. The solidproduced is triturated under benzene, filtered off, and dried, giving3.0 g. ofN-(N-[1-carboxyhept-1-yl]-carbamoyl)-2-phenylethenesulfonamide, m.p.142°-144°C.

Analysis -- Calc'd for C₁₇ H₂₄ N₂ O₅ S (percent): C, 55,41; H, 6.57; N,7.60. Found (percent): C, 55.86; H, 6.70; N, 7.37.

EXAMPLE XXVIII N-(4-[3-(p-hydroxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide

To a solution of 1.37 g. ofN-(4-[3-(p-methoxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamidein 30 ml. of methylene chloride is added 175 μl. of glacial acetic acid.The mixture is cooled to -60° C., and then 850 μl. of boron tribromideis added slowly. The reaction mixture is then allowed to warm to ambienttemperature. After a further 3 hours, it is washed with ice-cold water,and then it is extracted with 1N sodium hydroxide. The sodium hydroxideextract is washed with ether and then it is acidified using concentratedhydrochloric acid. This causes a gum to precipitate. The supernatantaqueous layer is poured off, and the gum is dissolved in methylenechloride. The solvent is dried using anhydrous sodium sulfate, and thenevaporated in vacuo to give 0.50 g. of crude product. The product ispurified by dissolving it in a small volume of acetone andreprecipitating it by adding hexane. Finally there is obtained 0.142 g.of pureN-(4-[3-(p-hydroxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide,m.p. 132-5° C.

Analysis -- Calc'd for C₂₃ H₂₈ N₂ O₄ S (percent): C, 64.47; H, 6.59; N,6.54. Found (percent): C, 64.08; H, 6.97; N, 6.40.

EXAMPLE XXIX

Reaction of the appropriateN-([(methoxyphenyl)alkyl]piperidinocarbonyl)alkenesulfonamide with borontribromide, according to the procedure of Example XXVIII, produces thefollowing compounds:

N-(4-[3-(m-hydroxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(4-[3-(o-hydroxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide,

N-(4-[2-(p-hydroxyphenyl)ethyl]piperidinocarbonyl-2-(p-chlorophenyl)ethenesulfonamide,

N-(4-[4-(m-hydroxyphenyl)butyl]piperidinocarbonyl)-1-(p-tolyl)propene-2-sulfonamideand

N-(4-[5-(m-hydroxyphenyl)pentyl]piperidinocarbonyl)-2-(p-bromophenyl)ethenesulfonamide,

respectively.

EXAMPLE XXXN-(4-[3-Phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide

A stirred mixture of 1.83 g. of 2-phenylethenesulfonamide, 1.3 ml. ofoxalyl chloride and 15 ml. of tetrahydrofuran is heated in an oil bathat 75°-80°C. for 1.5 hours, under an atmosphere of nitrogen. To thesolution obtained, is added 30 ml. of xylene, and the internaltemperature is raised to 138°C. over a 20 minute period, while allowingthe tetrahydorfuran and excess oxalyl chloride to distil out of thesolution. During this period, two further 5-ml. portions of xylene areadded. The resulting solution is maintained at ca. 138°C. for a further15 minutes, and then it is cooled to 85°C. To this xylene solution of2-phenylethenesulfonyl isocyanate is added 4.06 g. of4-(3-phenylpropyl)piperidine in small portions during 1 minute. Thereaction mixture is stirred at ambient temperature for 1.5 hours, andthen it is washed successively with 75 ml. of 1N hydrochloric acid andtwo 25-ml. portions of water. To the dried and filtered xylene solution,is then added 20 ml. of acetone followed by the dropwise addition of 120ml. of hexane. The precipitate which forms is removed by filtration,affording 2.89 g. (70% yield) of crude product. After recrystallizationfrom acetone/hexane, there is obtained 1.07 g. of the title compoundshowing a melting point of 125°-127°C.

EXAMPLE XXXI

Reaction of the appropriate alkenesulfonamide with oxalyl chloride,according to the procedure of Example XXX affords the followingisocyanates:

2-(o-fluorophenyl)ethenesulfonyl isocyanate,

2-(p-chlorophenyl)ethenesulfonyl isocyanate,

2-(p-bromophenyl)ethenesulfonyl isocyanate,

2-(m-tolyl)propene-1-sulfonyl isocyanate,

1-(p-methoxyphenyl)butene-2-sulfonyl isocyanate and

2-(p-trifluoromethylphenyl)ethenesulfonyl isocyanate, respectively.

Reaction of one of the above isocyanates with the requisite amine, alsoaccording to the procedure of Example XXX, produces the followingcompounds.

N-(4-[3-phenylpropyl]piperidinocarbonyl)-2-(2-fluorophenyl)ethenesulfonamide,

N-(4-[3-(p-tolyl)propyl]piperidinocarbonyl)-2-(p-chlorophenyl)ethenesulfonamide,

N-(4-[5-(m-methoxyphenyl)pentyl]piperidinocarbonyl)-2-(p-bromophenyl)ethenesulfonamide,

N-(2-methylpiperidinocarbonyl)-2-(m-tolyl)propene-1-sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-1-(p-methoxyphenyl)butene-2-sulfonamideand

N-(n,n-dibutylcarbamoyl)-2-(p-trifluoromethylphenyl)ethenesulfonamide,

respectively.

EXAMPLE XXXIIN-(4-[3-Phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide

A stirred mixture of 1.83 g. (0.01 mole) of 2-phenylethenesulfonamide,3.45 g. (0.025 mole) of potassium carbonate and 4.0 g. (0.015 mole) of4-(3-phenylpropyl)piperidinocarbonyl chloride, in 75 ml. of chloroformis heated under reflux for 22 hours. The solvent is then removed byevaporation in vacuo, and to the residue is added 75 ml of 0.5N sodiumhydroxide and 35 ml. of ether. The mixture is stirred for 1 hour, andthen the solid which remains undissolved is removed by filtration. Thisaffords 1.84 g. (ca. 41% yield) of the title compound as a mixture ofits sodium and potassium salts.

A 0.5-g. portion of the above crude product is dissolved in 6 ml. ofacetone and 3 ml. of water. The pH of the mixture is lowered to 2.0, andthe undissolved solid is removed by filtration. It is thenrecrystallized from acetone-hexane, giving 0.28 g. of the titlecompound, having melting point 127.5°-129°C.

EXAMPLE XXXIIIN-(4-[3-Phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide

A solution of 1.77 g. (7.5 mmole) of N-(N-propylcarbamoyl)-2-phenylethenesulfonamide, 3.0 g. (15 mmole) of 4-(3-phenylpropyl)piperidine and0.86 ml. (15 mmole) of acetic acid, in 10 ml. of N,N-dimethylformamideis heated at 100°-105°C. for 4 hours. The reaction solution is thencooled to 25°C., and 50 ml. of 1N hydrochloric acid, followed by 50 ml.of ether is added. The layers are separated, and to the ether phase isadded 50 ml. of 1N sodium hydroxide. This causes an oil to appear as anintermediate phase. The three layers are separated, and the aqueousphase is discarded. The ether phase is washed with water and thenevaporated in vacuo to give 2.3 g. of a viscous liquid. The intermediateoil phase is dissolved in 25 ml. of water, which is then acidified withconcentrated hydrochloric acid. The acidified aqueous phase is extractedwith ethyl acetate, and the extracts are washed with water and thenevaporated in vacuo. This affords 0.5 g. of a gummy residue.

The 2.3 g. of oil and the 0.5 g. of gummy residue are combined andchromatographed on a column of silica gel. The first few fractions arecombined and evaporated in vacuo, to give 0.3 g. of an oil. This latteroil is dissolved in 5 ml. of acetone, and 5 ml. of 1N sodium hydroxide,followed by 10 ml. of water, is added. This causes the crude product toprecipitate as its sodium salt. The sodium salt is dissolved in 3 ml. ofacetone, and 5 drops of concentrated hydrochloric acid, followed by 10ml. of water, are added. This solution is extracted with ethyl acetate.The dried extract is evaporated in vacuo, and the residue isrecrystallized from acetone-hexane, giving 12 mg. of the title compound,m.p. 119°-122°C. After two further recrystallizations fromacetone-hexane, the product has a melting point of 127.5°-129.5°C.

EXAMPLE XXXIV

A dry solid pharmaceutical composition is prepared by blending thefollowing materials together in the specified proportions by weight:

    ______________________________________                                        N-(1,2,3,4-tetrahydroisoquino-                                                                          50                                                  linocarbonyl)-2-phenylethene-                                                 sulfonamide                                                                   sodium citrate            25                                                  alginic acid              10                                                  polyvinylpyrrolidone      10                                                  magnesium stearate         5                                                  ______________________________________                                    

After the dried composition is thoroughly blended, tablets are punchedfrom the mixture, each tablet being of such size as to contain 100 mg.of the active ingredient.

Tablets are also prepared containing respectively 10, 25, 50 and 200 mg.of active ingredient, by chosing the appropriate proportions ofN-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenylethenesulfonamide andthe excipient blend in each case.

EXAMPLE XXXV

A dry solid pharmaceutical composition is prepared by combining thefollowing materials in the indicated proportions by weight:

    ______________________________________                                        N-(4-[3-phenylpropyl]piperidinocarbonyl)-                                                                250.0                                              2-phenylethenesulfonamide                                                     lactose                    190.2                                              dried corn starch          50.0                                               Sterotex K (a hydrogenated vegetable oil)                                                                9.8                                                ______________________________________                                    

The dry mixture is thoroughly agitated to obtain a completely uniformblend. Soft elastic and hard gelatin capsules containing thiscomposition are then prepared, employing sufficient material to provideeach capsule with 250 mg. of active ingredient.

Capsules are also prepared containing respectively 50, 100 and 500 mg.of active ingredient, by varying the proportions of sulfonamide andexcipient blend.

EXAMPLE XXXVI

To a stirred solution of 4.12 g. ofN-(4-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide in100 ml. of n-butanol, is added a solution prepared by dissolving 390 mg.of potassium in 10 ml. of n-butanol. The mixture is stirred for anadditional 15 minutes, and then the solvent is removed by evaporation invacuo. To the residue is added 250 ml. of diethyl ether, and the mixtureis stirred for 15 minutes. The solid is then filtered off, and driedunder vacuum, giving the potassium salt ofN-(4-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide.

EXAMPLE XXXVII

Normal, Sprague-Dawley (Charles River), male rats are fasted for 9hours. Test groups, each consisting of 5 animals, are then fed overnight(15-16 hours) with ground Purina rat chow, containing 0.2% of the testcompound. The following morning, the medicated food is withdrawn, andthen, after 1 hour, each rat is dosed with an oral gavage containing 50mg./kg. of the test compound. After a further 2 hours, a 300-mg./kg.dose of Triton WR-1339 (oxyethylated tertiaryoctylphenolformaldehydepolymer, Ruger Chemical Co., Philadelphia, Pa.) in saline isadministered to each rat, by injection into the tail vein. After afurther 2 hours, a second oral gavage containing 50 mg./kg. of the testcompound is given to each rat. After a further 4 hours, each rate isexxanguinated via the abdominal aorta under pentobarbital anesthesia.Control rats are treated in the same manner, except that they receiverat chow alone, and the two oral gavages contain no test compound.Control rats receive the same dose of Triton as the test animals.

Plasma is obtained fom the heparinized blood samples, and the plasmacholesterol concentrations are measured using the Auto-Analyser(Technicon method N-24a). The activity of a test compound is assessed bycomparing plasma cholesterol levels from rats treated with the testcompound and control rats. Results are shown below in Tabular form. Thereported results are calculated by subtracting the plasma cholesterolconcentration in treated rats from the control plasma cholesterol level,and expressing the difference as a percentage of the control value.

    ______________________________________                                                                  Percentage                                                                    Cholesterol                                         Test Compound             Fall                                                ______________________________________                                        N-(N-n-butylcarbamoyl)-2-(p-chloro-                                                                      8                                                  phenyl)ethenesulfonamide                                                      N-(piperidinocarbonyl)-2-phenylethene-                                                                   5                                                  sulfonamide                                                                   N-(N-[carboxymethyl]carbamoyl)-2-phenyl-                                                                 8                                                  ethenesulfonamide                                                             N-(N-cyclohexylcarbamoyl)-2-phenylethene-                                                               14                                                  sulfonamide                                                                   N-(N-[ethoxycarbonylmethyl]carbamoyl)-2-                                                                 9                                                  phenylethenesulfonamide                                                       N-(N,N-di[n-butyl]carbamoyl)-2-phenyl-                                                                   5                                                  ethenesulfonamide                                                             N-(4-benzylpiperidinocarbonyl)-2-phenyleth-                                                              5                                                  enesulfonamide                                                                N-(N-n-propylcarbamoyl)-1,1-diphenylethene-                                                             12                                                  sulfonamide                                                                   N-(N-allylcarbamoyl)-2-phenylethenesulfon-                                                              21                                                  amide                                                                         N-(N-methyl-N-[2-phenylethyl]carbamoyl)-2-                                                              13                                                  phenylethenesulfonamide                                                       N-(1-azacycloheptylcarbonyl)-2-phenylethene-                                                            16                                                  sulfonamide                                                                   N-(N,N-di[2-methylprop-1-yl]carbamoyl)-2-                                                               15                                                  phenylethenesulfonamide                                                       N-(morpholinocarbonyl)-1-phenylpropene-2-                                                                8                                                  sulfonamide                                                                   N-(N-[1-ethoxycarbonyl-2-methylprop-1-yl[-                                                              15                                                  carbamoyl)-2-phenylethenesulfonamide                                          N-(4-[3-phenylpropyl]piperidinocarbonyl)-                                                               30                                                  2-phenylethenesulfonamide                                                      "                        17                                                  "                         20                                                  "                         31                                                  ______________________________________                                    

EXAMPLE XXXVIII

A normal, adult, beagle dog, weighing approximately 10 kg., is fedPurina dog chow once daily, at 12:00 noon, for several days. Then on themornings of two consecutive days, the dog is bled from the jugular vein,and the plasma cholesterol concentrations are measured by the methodadapted for use in the Technicon Auto-Analyser. The mean of these valuesconstitutes the baseline plasma cholesterol level of that dog. The dogis then dosed orally, twice daily, with the test compound, whilecontinuing to feed the dog Purina dog chow once daily at 12:00 noon. Onthe morning of the sixth day after the start of administration of thetest compound, the dog is again bled from the jugular vein, and againthe plasma cholesterol level is measured using the TechniconAuto-Analyser. The level thus obtained is compared with the baselinevalue, in determining the hypolipidemic properties of the test compound.Results are shown below.

    __________________________________________________________________________                                              Plasma Cholesterol Level                                                      (mg./100 ml.)                                                     Dosage of                                                                              Sex     After administration                                         Test Compound                                                                          of      of test compound for           Compound                      (mg./kg.)                                                                              Dog                                                                              Baseline                                                                           6 days                         __________________________________________________________________________    N-(N-[n-butyl]carbamoyl)-2-phenylethenesulfonamide                                                          25       F  296  202                               "                          25       M  143  132                            N-(N-[m-tolyl]carbamoyl)-2-phenylethenesulfonamide                                                          25       F  149  129                               "                          25       M  135   94                            N-(N-[n-butyl]carbamoyl)-1-phenylpropene-2-sulfonamide                                                      25       F  157  136                               "                          25       M  130  128                            N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenyl-                                                        25       F  176  138                            ethenesulfonamide                                                                "                          25       M  155   84                               "                          2.5      M  137  128                               "                          2.5      M  159  146                               "                          1        F  160  157                               "                          1        M  190  143                            N-(4-[3-phenylpropyl]piperidinocarbonyl)-2-phenyl-                                                          5        F  120  114                            ethenesulfonamide                                                                "                          5        F  150  125                               "                          5        M  152  127                               "                          5        M  123  106                               "                          1        F  170  156                               "                          1        F  180  157                               "                          1        M  170  141                               "                          1        M  150  118                            N-(N-[carboxymethyl]carbamoyl)-2-phenylethenesulfonamide                                                    5        F  140  118                               "                          5        F  150  210                               "                          5        M  140  140                               "                          5        M  170  167                            __________________________________________________________________________

The following Preparations are provided, for the purpose of illustratingthe source of certain starting materials used in the foregoing Examples.

PREPARATION A 1-Phenylpropene-2-sulfonamide

To 17.5 ml. of N,N-dimethylformamide, cooled to 15°C., is addeddropwise, with stirring, during 30 minutes, 15.5 ml. of sulfurylchloride. The temperature is maintained below 25°C during the addition.The mixture is stirred for an additional 30 minutes at 25°C., and then11.3g. of 1-phenylpropene is added. The reaction mixture is heated at90°-93°C. for 75 minutes. It is then poured onto 400g. of crushed ice,and the product is extracted into methylene chloride. The solvent isdried using anhydrous sodium sulfate, and then it is evaporated in vacuoto give 18.7g. of 1-phenylpropene-2-sulfonyl chloride as a liquid.

The 1-phenylpropene-2-sulfonyl chloride is added to 200 ml. ofconcentrated ammonium hydroxide. After 1 hour the crystallineprecipitate which has formed is filtered off, and washed sequentiallywith water and hexane. The crude product so obtained is partitionedbetween 150 ml. of 1N sodium hydroxide and 50 ml. of ether, giving twoclear phases. The ether phase is removed and washed with 50 ml. ofwater, and then the water wash is added to the original aqueous phase.This combined solution is acidified using concentrated hydrochloricacid, which causes the product to precipitate. It is filtered off, andafter drying this affords 10.9g. of 1-phenylpropene-2-sulfonamide, m.p.138°-139.5°C.

PREPARATION B

Following the procedure of Preparation A, 2-phenylpropene is reactedwith sulfuryl chloride in N,N-dimethylformamide to give2-phenylpropene-1-sulfonyl chloride, which is then treated with ammoniato give 2-phenylpropene-1-sulfonamide, m.p. 101°-102.5°C.

When 1,1-diphenylethene reacts with sulfuryl chloride inN,N-dimethylformaide, followed by treatment with ammonia, according tothe procedure of Preparation A, there is obtained2,2-diphenylethenesulfonamide, m.p. 134°-135°C.

Analysis-- Calcd. for C₁₄ H₁₃ NO₂ S (percent): C, 64.86; H, 5.05; N,5.40. Found (percent): C, 64.73; H, 5.02; N, 5.26.

PREPARATION C

The procedure of Preparation A is repeated, except that the1-phenylpropene used therein is replaced by an equimolar amount of theappropriate phenylethene, phenylpropene, phenylbutene or diphenylethenederivative to produce the following sulfonamides:

2-phenylbut-1-ene-1-sulfonamide,

2-(p-chlorophenyl)propene-1-sulfonamide,

2-(p-methoxyphenyl)propene-1-sulfonamide,

1-(m-chlorophenyl)propene-2-sulfonamide,

2-(p-chlorophenyl)but-1-ene-1-sulfonamide,

1,2-diphenylethenesulfonamide,

3-phenylbut-2-ene-2-sulfonamide,

1-(p-chlorophenyl)propene-2-sulfonamide,

1,2-diphenylpropene-1-sulfonamide,

2-(p-tolyl)propene-1-sulfonamide,

2-(p-isopropylphenyl)propene-1-sulfonamide,

1-(p-ethoxyphenyl)propene-2-sulfonamide,

2-(p-fluorophenyl)propene-1-sulfonamide,

2-(p-butoxyphenyl)propene-1-sulfonamide,

1-phenylbut-1-ene-2-sulfonamide,

3-(m-chlorophenyl)but-2-ene-2-sulfonamide,

2-(p-chlorophenyl)-2-phenylethenesulfonamide,

2-(p-n-butylphenyl)propene-1-sulfonamide,

2-(m-methoxyphenyl)propene-1-sulfonamide,

2-(p-biphenylyl)propene-1-sulfonamide,

2,2-diphenylethenesulfonamide,

2-(m-chlorophenyl)propene-1-sulfonamide,

2-(m-bromophenyl)propene-1-sulfonamide,

2-(m-tolyl)propene-1-sulfonamide,

1-(o-chlorophenyl)propene-2-sulfonamide,

1-(p-fluorophenyl)propene-2-sulfonamide,

1-(p-tolyl)propene-2-sulfonamide,

1-(m-methoxyphenyl)propene-2-sulfonamide,

2-(p-tolyl)but-1-ene-1-sulfonamide,

2-(m-methoxyphenyl)but-1-ene-1-sulfonamide,

1-(p-chlorophenyl)but-1-ene-2-sulfonamide,

1-(m-methoxyphenyl)but-1-ene-2-sulfonamide and

3-(p-chlorophenyl)but-2-ene-2-sulfonamide,

respectively.

PREPARATION D

N,N-Diphenylcarbamoyl chloride is reacted withN-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine, essentiallyaccording to the procedure given McManus et al., J. Med. Chem., 8, 766(1965), for the preparation of 1,1-diphenyl-3-cycloheptylurea. Theproduct is1,1-diphenyl-3-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)urea, m.p.109°-111°C.

Analysis-- Calcd. for C₂₀ H₂₂ N₂ O₂ (percent): C, 74.49; H, 6.89; N,8.68. Found (percent): C, 74.28; H, 6.93; N, 8.61.

In a similar manner, N,N-diphenylcarbamoyl chloride andN-(exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine react to produce1,1-diphenyl-3-(exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)urea, m.p.128°-130°C.

Analysis-- Calcd. for C₂₀ H₂₂ N₂ O₂ (percent): C, 74.49; H, 6.89; N,8.68. Found (percent): C, 74.70; H, 6.75; N, 8.87.

PREPARATION E Endo. and exo-isomers ofN-(7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine

To a stirred solution of 212g. of acrylonitrile, 272g. of furan and 50mg. of hydroquinone, in 1 liter of benzene, is added a solution of 55ml. of titanium tetrachloride in 500 ml. of benzene. The addition iscarried out at such a rate that the internal reaction temperature doesnot exceed 35°C. The reaction mixture is then stirred at ambienttemperature for 5 days. It is then treated with 500 ml. of 0.5Nhydrochloric acid. After filtration, the aqueous phase is removed andextracted with benzene. The two benzene solutions are then combined,washed with water, dried using anhydrous sodium sulfate, and thenevaporated in vacuo. This affords 156.3g. of a mixture of endo- andexo-7-oxabicyclo[2.2.1]hept-2-en-5ylcyanide.

A 130-g. sample of the above mixture of isomers is dissolved in 1 literof acetone, and hydrogenated at 50 p.s.i. in the presence of 2g. ofpalladium-on-barium sulfate. The catalyst is removed by filtration, andthe solvent by evaporation under reduced pressure. The residual oil isfractionally distilled to give 55.5g. of pureendo-7-oxabicyclo[2.2.1]heptan-2-ylcyanide, b.p. 45°C. (0.1 mm. Hg), and37.9g. of pure exo-7-oxabicyclo[2.2.1]heptan-2-ylcyanide, b.p. 48°C.(0.02 mm. Hg). A small fraction weighing 14.7g., and consisting of anendo-exo mixture, is also obtained.

Analysis.-- Calcd. for C₇ H₉ NO (percent): C, 68.27; H, 7.37; N, 11.37.Found for endo-isomer (percent): C, 67.96; H, 7.21; N, 11.37. Found forexo-isomer (percent): C, 68.32; H, 7.42; N, 11.64.

To a stirred solution of 54.3g. of endo-7-oxabicyclo[2.2.1]heptan-2-ylcyanide in 500 ml. of methanol, is added 24 ml. of aslurry of Raney nickel in methanol, followed by the dropwise addition ofa solution of 33.2g. of sodium borohydride in 11- ml. of 4N sodiumhydroxide. During the latter addition step, external cooling is appliedto maintain an internal temperature of 40°-50°C. At the end of theaddition the mixture is stirred for a further 20 minutes, and then thesolids are filtered off. The filtrate is evaporated in vacuo, and theresidue obtained is suspended in 500 ml. of 1N sodium hydroxide. Themixture is extracted several times with chloroform, and then thecombined extracts are dried and evaporated giving 55.5g. ofN-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine, b.p. 90°C. (10mm.Hg).

A sample of exo-7-oxabicyclo[2.2.1]heptan-2-ylmethylcyanide is reducedby treatment with Raney nickel and sodium borohydride in methanol asdescribed for the endo-isomer. There is obtained a high yield ofN-(exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine, b.p. 92°-96°C.(14-16mm. Hg).

PREPARATION F 4-(3-[p-Methoxyphenyl]propyl)pyridine

To a stirred solution of 3.04 g. of 2-(p-methoxyphenyl)ethanol in 10 ml.of benzene, is added dropwise, a solution of 0.72 ml. of phosphorustribromide in 10 ml. of benzene, at ambient temperature. The mixture isthen heated at 60°C. for 1 hour. After being cooled to ambienttemperature again, the reaction mixture is poured onto 50 g. of crushedice. A small amount of ether is added, and then the organic phase isseparated off, washed sequentially with 0.5N sodium hydroxide and water,and evaporated to dryness. This affords 2.8 g. of2-(p-methoxyphenyl)ethyl bromide as an oil.

The above oil is dissolved in 15 ml. of ether, which is then addeddropwise to 243 mg. of magnesium turnings covered with 10 ml. of ether.A few crystals of iodine are added, and then the solvent is refluxeduntil almost all the magnesium has reacted. This gives an etherealsolution of 2-(p-methoxyphenyl)ethylmagnesium bromide.

The above-described Grignard solution is added dropwise, at 0.°C., to astirred solution of 1.04 g. of 4-cyanopyridine in 15 ml. of ether. Atthe end of the addition, the reaction mixture is refluxed for 4 hoursand then it is stirred at ambient temperature overnight. The reaction isquenched with ice water, and the aqueous phase is acidified usingconcentrated hydrochloric acid. The aqueous phase is then separated off,and heated at 85°-90°C. for 1 hour. It is cooled back to ambienttemperature, and extracted with chloroform, followed by ether. Thecombined organic extracts are dried using anhydrous magnesium sulfate,and then evaporated in vacuo, giving the product as an orange-coloredoil. The product is 2-(p-methoxyphenyl)ethyl 4-pyridyl ketone.

The above-described ketone (800 mg.) is heated under reflux for 2 hourswith 850 mg. of hydrazine hydrate. At this point 1.6 g. of powderedpotassium hydroxide is added and the reflux is continued for a further 2hours. The reaction mixture is then cooled to ambient temperature,diluted with 20 ml. of water, and extracted with ether. The dried etherextract is evaporated to dryness, leaving 260 mg. of4-(3-[p-methoxyphenyl]propyl)pyridine.

PREPARATION G

Starting with the appropriate cyanopyridine and (hydroxyalkyl)benzenecompound, and following the procedure of Preparation F, the followingcompounds are produced:

3-(3-phenylpropyl)pyridine,

2-(3-phenylpropyl)pyridine,

4-(2-[p-isopropoxyphenyl]ethyl)pyridine,

3-(3-[p-butoxyphenyl]propyl)pyridine,

4-(3-[p-isopropylphenyl]propyl)pyridine,

4-(3-[p-tert-butylphenyl]propyl)pyridine,

4-(m-methylbenzyl)pyridine,

4-(3-[m-methoxyphenyl]propyl)pyridine,

4-(3-[o-methoxyphenyl]porpyl)pyridine,

4-(2-[p-methoxyphenyl]ethyl)pyridine,

4-(4-[m-methoxyphenyl]butyl)pyridine,

4-(3-[p-tolyl]propyl)pyridine,

4-(5-[m-methoxyphenyl]pentyl)pyridine,

4-(4-phenylbutyl)pyridine

4-(5-phenylpentyl)pyridine,

4-(2-phenylprop-1-yl)pyridine and

4-(2-phenylbut-1-yl)pyridine,

respectively

PREPARATION H 4-(3-[p-Methoxyphenyl]propyl)piperidine

A solution of 2.27 g. of 4-(3-[p-methoxyphenyl]propyl)piperidine in 50ml. of 1.0N hydrochloric acid is hydrogenated at 45 psi, at ambienttemperature, in the presence of 150 mg. of platinum oxide. After 20hours the theoretical amount of hydrogen has been absorbed, and thecatalyst is filtered off. The aqueous filtrate is basified with 5Nsodium hydroxide, and then it is extracted with ether. The extract isdried and evaporated in vacuo, leaving 2.2 g. of an oil. The oil slowlysolidifies, giving 4-(3-[p-methoxyphenyl]propyl)piperidine, mp 65°-70°C.

PREPARATION I

Hydrogenation of the pyridine derivatives listed in Preparation G,according to the procedure of Preparation H, produces the followingpiperidine compounds:

3-(3-phenylpropyl)piperidine,

2-(3-phenylpropyl)piperidine,

4-(2-[p-isopropoxyphenyl]ethyl)piperidine

3-(3-[p-butoxyphenyl]propyl)piperidine,

4-(3-[p-isopropylphenyl]propyl)piperidine,

4-(3-[p-tert-butylphenyl]propyl)piperidine,

4-(m-methylbenzyl)piperidine

4-(3-[m-methoxyphenyl]propyl)piperidine,

4-(3-[o-methoxyphenyl]propyl)piperidine,

4-(2-[p-methoxyphenyl]ethyl)piperidine,

4-(4-[m-methoxyphenyl]butyl)piperidine,

4-(3-[p-tolyl]propyl)piperidine,

4-(5-[m-methoxyphenyl]pentyl)piperidine,

4-(4-phenylbutyl)piperidine

4-(5-phenylpentyl)piperidine,

4-(2-phenylprop-1-yl)piperidine and

4-(2-phenylbut-1-yl)piperidine,

respectively.

PREPARATION J 4-(3-Phenylpropyl)piperidinocarbonyl Chloride

Phosgene is passed into 150 ml. of dry toluene at 0°C. until 17 g. ofgas has been absorbed. The cooling bath is removed, and to the phosgenesolution is added, dropwise, with stirring, during 1 hour, a solutionprepared from 27.6. g. of 4-(3-phenylpropyl)piperidine, and 12.3 ml. ofpyridine and 100 ml. of toluene. After the end of the addition, thereaction mixture is stored at ambient temperature for 16 hours. At thispoint, the reaction mixture is filtered, and the filtrate is evaporatedin vacuo, leaving 39 g. of the title compound in crude state. Theproduct is contaminated with toluene, but it is sufficiently pure forcoupling with alkenesulfonamides.

What is claimed is:
 1. A compound selected from the group consisting of##SPC13##and the salts thereof; wherein X is selected from the groupconsisting of hydrogen, chloro and methyl; A and B are each selectedfrom the group consisting of hydrogen, methyl and ethyl; and Z isselected from the group consisting of 4-methoxypiperidino,4-carboxypiperidino, 4-phenylpiperidino, alkylpiperidino having from oneto three carbon atoms in said alkyl group, (phenylalkyl)piperidinohaving from one to five carbon atoms in said alkyl group and([substituted phenyl]-alkyl)piperidino having from one to five carbonatoms in said alkyl group, said substituted phenyl being substituted bya moiety selected from the group consisting of hydroxy, alkyl havingfrom one to four carbon atoms and alkoxy having from one to four carbonatoms.
 2. A compound according to claim 1, wherein A and B are eachhydrogen.
 3. A compound according to claim 2, wherein Z is selected fromthe group consisting of 4-(ω-phenylalkyl)piperidino having from one tofive carbon atoms in said alkyl group and 4-(ω-[substitutedphenyl]alkyl)piperidino having from one to five carbon atoms in saidalkyl group, said substituted phenyl being substituted by a moietyselected from the group consisting of hydroxy, alkyl having from one tofour carbon atoms and alkoxy having from one to four carbon atoms.
 4. Acompound according to claim 3, wherein Z is the said4-(ω-phenylalkyl)piperidino.
 5. A compound according to claim 4, whereinX is hydrogen.
 6. The compound according to claim 5, wherein Z is4-(3-phenylpropyl)piperidino.